Heterocyclic compounds useful as modulators of acetylcholine receptors

ABSTRACT

The present invention aims to provide a compound that may be useful for the prophylaxis or treatment of constipation and the like. The present invention provides a compound represented by the following formula (I):wherein each symbol is as described in the specification, or a salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. Application No. 16/606,043,which is the U.S. National Stage of PCT/JP2018/016382, filed Apr. 17,2018, which claims priority to JP 2017-081919, filed Apr. 18, 2017.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound possibly havinga cholinergic muscarinic M1 receptor positive allosteric modulatoractivity and possibly useful as a medicament such as a prophylactic ortherapeutic drug for constipation and the like. As used herein, thepositive allosteric modulator activity refers to an action to potentiatereceptor function by binding to a moiety different from that of anendogenous activator (acetylcholine for this receptor).

Background of the Invention

Acetylcholine is a neurotransmitter that induces signal transduction inthe central nervous system and the neuromuscular connections (theparasympathetic nerve and motor nerve). In the gastrointestinal tract,myenteric plexus, submucosal plexus and the like form a neural networkand control gastrointestinal function. Of these, acetylcholine is amajor neurotransmitter in the gastrointestinal function and plays a keyrole in the gastrointestinal motility.

Acetylcholine receptor is classified into a ligand dependent ion channel(cholinergic nicotinic receptor) and a G-protein-conjugated receptor(cholinergic muscarinic receptor). The cholinergic muscarinic receptoris one kind of receptor for excitatory neurotransmitter acetylcholine,and was named based on the selective activation of the receptor bymuscarine. The muscarinic receptor is further classified into subtypesof M1 to M5, and the M1 receptor is known to be widely distributedmainly in the brain. On the other hand, expression of M1 receptor in thegastrointestinal nerve plexus is also known and its role of regulatingthe functions of the gastrointestinal tract has been pointed out(non-patent document 1). From the studies in recent years, promotion ofgastrointestinal motility by cholinergic M1 receptor agonist has alsobeen reported.

Generally, peristalsis in the gastrointestinal tract consists ofcoordinated contraction and relaxation at adjacent sites. It is alsoknown that the cholinergic M1 receptor is expressed in both theexcitatory nerve and inhibitory nerve in the gastrointestinal nerveplexus (non-patent document 1).

WO2014/102233 (patent document 1) discloses the following compound whichis a COMT inhibitor and useful for the treatment of Parkinson’s disease,dementia, depression, schizophrenia and the like.

wherein each symbol is as defined in the document.

WO2007/020411 (patent document 2) discloses the following compound whichis a cytokine inhibitor and useful for the treatment of rheumatoidarthritis, asthma, inflammatory bowel disease, multiple sclerosis, AIDS,sepsis shock and the like.

wherein each symbol is as defined in the document.

WO2006/090143 (patent document 3) discloses the following compound whichis a cytokine inhibitor and useful for the treatment of rheumatoidarthritis, asthma, inflammatory bowel disease, multiple sclerosis, AIDS,sepsis shock and the like.

wherein each symbol is as defined in the document.

WO2001/007436 (patent document 4) discloses the following compound whichis an FXa inhibitor and useful for the treatment of Alzheimer’s diseaseand the like.

wherein each symbol is as defined in the document.

WO2000/032590 (patent document 5) discloses the following compound whichis an FXa inhibitor and useful for the treatment of Alzheimer’s diseaseand the like.

wherein each symbol is as defined in the document.

WO99/37304 (patent document 6) discloses the following compound which isan FXa inhibitor and useful for the treatment of Alzheimer’s disease andthe like.

wherein each symbol is as defined in the document.

WO 2013/129622 (patent document 7) discloses the following compoundhaving a cholinergic muscarinic M1 receptor positive allostericmodulator (M1PAM) activity and useful for the treatment of Alzheimer’sdisease, schizophrenia, pain, sleep disorder and the like.

wherein each symbol is as defined in the document.

WO2014/077401 (patent document 8) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer’sdisease, schizophrenia, pain, sleep disorder and the like.

wherein each symbol is as defined in the document.

WO2015/174534 (patent document 9) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer’sdisease, schizophrenia, pain, sleep disorder, Parkinson’s diseasedementia, Lewy body dementia and the like.

wherein each symbol is as defined in the document.

WO2015/163485 (patent document 10) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer’sdisease, schizophrenia, pain, sleep disorder, Parkinson’s diseasedementia, Lewy body dementia and the like.

wherein each symbol is as defined in the document.

WO2016/208775 (patent document 11) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer’sdisease, schizophrenia, pain, sleep disorder, Parkinson’s diseasedementia, Lewy body dementia and the like.

wherein each symbol is as defined in the document.

WO2015/190564 (patent document 12) discloses the following compoundhaving an M1PAM activity and useful for the treatment of Alzheimer’sdisease, schizophrenia, pain, sleep disorder, Parkinson’s diseasedementia, Lewy body dementia and the like.

wherein each symbol is as defined in the document.

Non-patent document 2 discloses the following compounds.

DOCUMENT LIST Patent Documents

-   patent document 1: WO 2014/102233-   patent document 2: WO 2007/020411-   patent document 3: WO 2006/090143-   patent document 4: WO 2001/007436-   patent document 5: WO 2000/032590-   patent document 6: WO 99/37304-   patent document 7: WO 2013/129622-   patent document 8: WO 2014/077401-   patent document 9: WO 2015/174534-   patent document 10: WO 2015/163485-   patent document 11: WO 2016/208775-   patent document 12: WO 2015/190564

Non-Patent Documents

-   non-patent document 1: Journal of Chemical Neuroanatomy, 2007 Jul,    33(4), 193-201-   non-patent document 2: ACS Chemical Neuroscience, 2016, 7(5),    647-661

SUMMARY OF THE INVENTION Problems to Be Solved by the Invention

The development of a compound having a cholinergic muscarine M1 receptor(M1 receptor) positive allosteric modulator activity and useful as aprophylactic or therapeutic agent for constipation, for example,constipation associated with neurological disease (e.g., Parkinson’sdisease, spinal cord injury, multiple sclerosis), age-relatedconstipation, opioid-induced constipation and the like is desired. Asused herein, the positive allosteric modulator activity means an actionto bind to a site different from an endogenous activator (acetylcholinein this receptor) and potentiate the receptor function.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the aforementioned problems and found that a compound representedby the following formula (I) may have a cholinergic muscarinic M1receptor positive allosteric modulator activity, which resulted in thecompletion of the present invention.

Therefore, the present invention relates to the following.

[1] A compound represented by the formula (I):

wherein

-   X¹ is CH or N;-   X² is CR¹⁰ or N;-   R¹⁰ is a hydrogen atom or a halogen atom;-   R¹ and R² are each independently a hydrogen atom, a halogen atom, an    optionally substituted C₁₋₆ alkyl group or an optionally substituted    C₁₋₆ alkoxy group;-   R³ and R⁴ are each independently a hydrogen atom, a halogen atom, a    hydroxy group, an optionally substituted C₁₋₆ alkyl group or an    optionally substituted C₁₋₆ alkoxy group;-   R⁵ and R⁶ are each independently a hydrogen atom or a halogen atom;-   R⁷ is a substituted monocyclic heterocyclic group, an optionally    substituted carbamoyl group, an optionally substituted C₁₋₆ alkyl    group, a carboxy group, a substituted C₁₋₆ alkoxy group, an    optionally substituted heteroaryloxy group or a group represented by    N(R⁸)COR⁹ wherein R⁸ is a hydrogen atom or an optionally substituted    C₁₋₆ alkyl group and R⁹ is an optionally substituted C₁₋₆ alkyl    group,

or a salt thereof (sometimes to be abbreviated as “compound (I)” in thepresent specification).

The compound described in the above-mentioned [1], wherein

-   R¹ is a hydrogen atom, a halogen atom or a C₁₋₆ alkyl group;-   R² is a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group;-   R³ and R⁴ are each independently a hydrogen atom or a halogen atom;-   R⁵ and R⁶ are each independently a hydrogen atom or a halogen atom;    and-   R⁷ is    -   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group        substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3            substituents selected from a halogen atom, a C₃₋₁₀            cycloalkyl group, a C₁₋₆ alkoxy group and a mono- or di-C₁₋₆            alkyl-carbamoyl group,        -   (b) a C₃₋₁₀ cycloalkyl group, and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group,    -   (2) a carbamoyl group substituted by 1 or 2 substituents        selected from        -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3            substituents selected from            -   (i) a halogen atom,            -   (ii) a C₃₋₁₀ cycloalkyl group optionally substituted by                1 to 3 hydroxy groups,            -   (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group,            -   (iv) a C₁₋₆ alkoxy group,            -   (v) a hydroxy group,            -   (vi) a 3- to 8-membered monocyclic non-aromatic                heterocyclic group optionally substituted by one oxo                group, and            -   (vii) a C₁₋₆ alkylsulfonyl group,        -   (b) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to            3 substituents selected from a halogen atom, an optionally            halogenated C₁₋₆ alkyl group and a cyano group, and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group optionally substituted by 1 to 3 substituents selected            from a C₁₋₆ alkyl group, an oxo group and a hydroxy group,    -   (3) an azetidin-1-ylcarbonyl group optionally substituted by 1        to 3 substituents selected from an optionally halogenated C₁₋₆        alkyl group, a hydroxy group and a C₁₋₆ alkoxy group,    -   (4) a C₁₋₆ alkyl group, or    -   (5) a carboxy group,

    or a salt thereof.

The compound described in the above-mentioned [1] or [2], wherein

-   R⁷ is a carbamoyl group substituted by 1 or 2 substituents selected    from    -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom,        -   (ii) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to            3 hydroxy groups,        -   (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group,        -   (iv) a C₁₋₆ alkoxy group,        -   (v) a hydroxy group,        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group optionally substituted by one oxo group, and        -   (vii) a C₁₋₆ alkylsulfonyl group,    -   (b) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3        substituents selected from a halogen atom, an optionally        halogenated C₁₋₆ alkyl group and a cyano group, and    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group optionally substituted by 1 to 3 substituents selected        from a C₁₋₆ alkyl group, an oxo group and a hydroxy group,

    or a salt thereof.

The compound described in the above-mentioned [1], wherein

-   R¹ is a halogen atom or a C₁₋₆ alkyl group;-   R² is a C₁₋₆ alkyl group;-   R³ is a hydrogen atom;-   R⁴ is a hydrogen atom;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom or a halogen atom; and-   R⁷ is    -   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group        substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3            substituents selected from a C₃₋₁₀ cycloalkyl group and a            C₁₋₆ alkoxy group,        -   (b) a C₃₋₁₀ cycloalkyl group, and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group,    -   (2) a carbamoyl group substituted by 1 or 2 substituents        selected from        -   (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3            substituents selected from (i) a C₃₋₁₀ cycloalkyl group            optionally substituted by 1 to 3 hydroxy groups, (ii) a            mono-or di-C₁₋₆ alkyl-carbamoyl group, (iii) a C₁₋₆ alkoxy            group, (iv) a hydroxy group, (v) a 3- to 8-membered            monocyclic non-aromatic heterocyclic group optionally            substituted by one oxo group, and (vi) a C₁₋₆ alkylsulfonyl            group,        -   (b) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to            3 halogen atoms, and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group optionally substituted by 1 to 3 substituents selected            from a C₁₋₆ alkyl group and an oxo group, or    -   (3) an azetidin-1-ylcarbonyl group optionally substituted by 1        to 3 C₁₋₆ alkoxy groups,

    or a salt thereof.

The compound described in the above-mentioned [1], wherein

-   R¹ is a halogen atom or a C₁₋₆ alkyl group;-   R² is a C₁₋₆ alkyl group;-   R³ is a hydrogen atom;-   R⁴ is a hydrogen atom;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom or a halogen atom; and-   R⁷ is    -   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group        substituted by 1 to 3 C₁₋₆ alkyl groups, or    -   (2) a carbamoyl group substituted by a C₁₋₆ alkyl group        optionally substituted by one substituent selected from a C₁₋₆        alkoxy group and a 3- to 8-membered monocyclic non-aromatic        heterocyclic group,

    or a salt thereof.

3-((3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one,

or a salt thereof.

2-Fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-methylbenzamide,

or a salt thereof.

6-((6-(1,3-Dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one,

or a salt thereof.

3-((3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one,

or a salt thereof.

4-((8-Chloro-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)methyl)-2-fluoro-N-methylbenzamide,

or a salt thereof.

2-Fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(2-methoxyethyl)benzamide,

or a salt thereof.

2-Fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(((R)-tetrahydrofuran-2-yl)methyl)benzamide,

or a salt thereof.

A medicament comprising the compound described in the above-mentioned[1] or a salt thereof.

The medicament described in the above-mentioned [13], which is acholinergic muscarinic M1 receptor positive allosteric modulator.

The medicament described in the above-mentioned [13], which is aprophylactic or therapeutic agent for constipation.

A method of cholinergic muscarinic M1 receptor positive allostericmodulation in a mammal, comprising administering an effective amount ofthe compound described in the above-mentioned [1] or a salt thereof tosaid mammal.

A method for the prophylaxis or treatment of constipation in a mammal,comprising administering an effective amount of the compound describedin the above-mentioned [1] or a salt thereof to the mammal.

Use of the compound described in the above-mentioned [1] or a saltthereof in the production of a prophylactic or therapeutic agent forconstipation.

The compound described in the above-mentioned [1] or a salt thereof foruse in the prophylaxis or treatment of constipation.

Effect of the Invention

The compound of the present invention may have a cholinergic muscarinicM1 receptor positive allosteric modulator activity, and may be useful asa medicament such as a prophylactic or therapeutic drug for, forexample, constipation, such as constipation associated with neurologicaldisease (e.g., Parkinson’s disease, spinal cord injury, multiplesclerosis), age-related constipation, opioid-induced constipation andthe like.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each substituent used in the present specification isdescribed in detail in the following. Unless otherwise specified, eachsubstituent has the following definition.

In the present specification, examples of the “halogen atom” includefluorine, chlorine, bromine and iodine.

In the present specification, examples of the “C₁₋₆ alkyl group” includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and2-ethylbutyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl group” include a C₁₋₆ alkyl group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and6,6,6-trifluorohexyl.

In the present specification, examples of the “C₂₋₆ alkenyl group”include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and5-hexenyl.

In the present specification, examples of the “C₂₋₆ alkynyl group”include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.2.1]octyl and adamantyl.

In the present specification, examples of the “optionally halogenatedC₃₋₁₀ cycloalkyl group” include a C₃₋₁₀ cycloalkyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include cyclopropyl, 2,2-difluorocyclopropyl,2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the present specification, examples of the “C₃₋₁₀ cycloalkenyl group”include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

In the present specification, examples of the “C₆₋₁₄ aryl group” includephenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

In the present specification, examples of the “C₇₋₁₆ aralkyl group”include benzyl, phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of the “C₁₋₆ alkoxy group”include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkoxy group” include a C₁₋₆ alkoxy group optionally having 1 to 7,preferably 1 to 5, halogen atoms. Specific examples thereof includemethoxy, difluoromethoxy, trifluoromethoxy, ethoxy,2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy,4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In the present specification, examples of the “C₃₋₁₀ cycloalkyloxygroup” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

In the present specification, examples of the “C₁₋₆ alkylthio group”include methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylthio group” include a C₁₋₆ alkylthio group optionally having 1to 7, preferably 1 to 5, halogen atoms. Specific examples thereofinclude methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio and hexylthio.

In the present specification, examples of the “C₁₋₆ alkyl-carbonylgroup” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl,pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl,hexanoyl and heptanoyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkyl-carbonyl group” include a C₁₋₆ alkyl-carbonyl groupoptionally having 1 to 7, preferably 1 to 5, halogen atoms. Specificexamples thereof include acetyl, chloroacetyl, trifluoroacetyl,trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the “C₁₋₆ alkoxy-carbonylgroup” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl andhexyloxycarbonyl.

In the present specification, examples of the “C₆₋₁₄ aryl-carbonylgroup” include benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the “C₇₋₁₆ aralkyl-carbonylgroup” include phenylacetyl and phenylpropionyl.

In the present specification, examples of the “5- to 14-memberedaromatic heterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl,thenoyl and furoyl.

In the present specification, examples of the “3- to 14-memberednon-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl,piperidinylcarbonyl and pyrrolidinylcarbonyl.

In the present specification, examples of the “mono- or di-C₁₋₆alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N-methylcarbamoyl.

In the present specification, examples of the “mono- or di-C₇₋₁₆aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.

In the present specification, examples of the “C₁₋₆ alkylsulfonyl group”include methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl andtert-butylsulfonyl.

In the present specification, examples of the “optionally halogenatedC₁₋₆ alkylsulfonyl group” include a C₁₋₆ alkylsulfonyl group optionallyhaving 1 to 7, preferably 1 to 5, halogen atoms. Specific examplesthereof include methylsulfonyl, difluoromethylsulfonyl,trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl,pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the “C₆₋₁₄ arylsulfonyl group”include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

In the present specification, examples of the “substituent” include ahalogen atom, a cyano group, a nitro group, an optionally substitutedhydrocarbon group, an optionally substituted heterocyclic group, an acylgroup, an optionally substituted amino group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, an optionally substitutedhydroxy group, an optionally substituted sulfanyl (SH) group and anoptionally substituted silyl group.

In the present specification, examples of the “hydrocarbon group”(including “hydrocarbon group” of “optionally substituted hydrocarbongroup”) include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀ cycloalkenyl group, a C₆₋₁₄aryl group and a C₇₋₁₆ aralkyl group.

In the present specification, examples of the “optionally substitutedhydrocarbon group” include a hydrocarbon group optionally havingsubstituent(s) selected from the following substituent group A.

Substituent Group A

-   (1) a halogen atom,-   (2) a nitro group,-   (3) a cyano group,-   (4) an oxo group,-   (5) a hydroxy group,-   (6) an optionally halogenated C₁₋₆ alkoxy group,-   (7) a C₆₋₁₄ aryloxy group (e.g., phenoxy, naphthoxy),-   (8) a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy),-   (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,    pyridyloxy),-   (10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g.,    morpholinyloxy, piperidinyloxy),-   (11) a C₁₋₆ alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),-   (12) a C₆₋₁₄ aryl-carbonyloxy group (e.g., benzoyloxy,    1-naphthoyloxy, 2-naphthoyloxy),-   (13) a C₁₋₆ alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,    ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),-   (14) a mono- or di-C₁₋₆ alkyl-carbamoyloxy group (e.g.,    methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,    diethylcarbamoyloxy),-   (15) a C₆₋₁₄ aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy,    naphthylcarbamoyloxy),-   (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group    (e.g., nicotinoyloxy),-   (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group    (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy),-   (18) an optionally halogenated C₁₋₆ alkylsulfonyloxy group (e.g.,    methylsulfonyloxy, trifluoromethylsulfonyloxy),-   (19) a C₆₋₁₄ arylsulfonyloxy group optionally substituted by a C₁₋₆    alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy),-   (20) an optionally halogenated C₁₋₆ alkylthio group,-   (21) a 5- to 14-membered aromatic heterocyclic group,-   (22) a 3- to 14-membered non-aromatic heterocyclic group,-   (23) a formyl group,-   (24) a carboxy group,-   (25) an optionally halogenated C₁₋₆ alkyl-carbonyl group,-   (26) a C₆₋₁₄ aryl-carbonyl group,-   (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,-   (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,-   (29) a C₁₋₆ alkoxy-carbonyl group,-   (30) a C₆₋₁₄ aryloxy-carbonyl group (e.g., phenyloxycarbonyl,    1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),-   (31) a C₇₋₁₆ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,    phenethyloxycarbonyl),-   (32) a carbamoyl group,-   (33) a thiocarbamoyl group,-   (34) a mono- or di-C₁₋₆ alkyl-carbamoyl group,-   (35) a C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl),-   (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,    pyridylcarbamoyl, thienylcarbamoyl),-   (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group    (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl),-   (38) an optionally halogenated C₁₋₆ alkylsulfonyl group,-   (39) a C₆₋₁₄ arylsulfonyl group,-   (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g.,    pyridylsulfonyl, thienylsulfonyl),-   (41) an optionally halogenated C₁₋₆ alkylsulfinyl group,-   (42) a C₆₋₁₄ arylsulfinyl group (e.g., phenylsulfinyl,    1-naphthylsulfinyl, 2-naphthylsulfinyl),-   (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g.,    pyridylsulfinyl, thienylsulfinyl),-   (44) an amino group,-   (45) a mono- or di-C₁₋₆ alkylamino group (e.g., methylamino,    ethylamino, propylamino, isopropylamino, butylamino, dimethylamino,    diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),-   (46) a mono- or di-C₆₋₁₄ arylamino group (e.g., phenylamino),-   (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,    pyridylamino),-   (48) a C₇₋₁₆ aralkylamino group (e.g., benzylamino),-   (49) a formylamino group,-   (50) a C₁₋₆ alkyl-carbonylamino group (e.g., acetylamino,    propanoylamino, butanoylamino),-   (51) a (C₁₋₆ alkyl) (C₁₋₆ alkyl-carbonyl) amino group (e.g.,    N-acetyl-N-methylamino),-   (52) a C₆₋₁₄ aryl-carbonylamino group (e.g., phenylcarbonylamino,    naphthylcarbonylamino),-   (53) a C₁₋₆ alkoxy-carbonylamino group (e.g., methoxycarbonylamino,    ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino,    tert-butoxycarbonylamino),-   (54) a C₇₋₁₆ aralkyloxy-carbonylamino group (e.g.,    benzyloxycarbonylamino),-   (55) a C₁₋₆ alkylsulfonylamino group (e.g., methylsulfonylamino,    ethylsulfonylamino),-   (56) a C₆₋₁₄ arylsulfonylamino group optionally substituted by a    C₁₋₆ alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino),-   (57) an optionally halogenated C₁₋₆ alkyl group,-   (58) a C₂₋₆ alkenyl group,-   (59) a C₂₋₆ alkynyl group,-   (60) a C₃₋₁₀ cycloalkyl group,-   (61) a C₃₋₁₀ cycloalkenyl group and-   (62) a C₆₋₁₄ aryl group.

The number of the above-mentioned substituents in the “optionallysubstituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to3. When the number of the substituents is two or more, the respectivesubstituents may be the same or different.

In the present specification, examples of the “heterocyclic group”(including “heterocyclic group” of “optionally substituted heterocyclicgroup”) include (i) an aromatic heterocyclic group, (ii) a non-aromaticheterocyclic group and (iii) a 7- to 10-membered bridged heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” (including “5- to 14-membered aromatic heterocyclic group”)include a 5- to 14-membered (preferably 5-to 10-membered) aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “aromatic heterocyclic group” include 5- or6-membered monocyclic aromatic heterocyclic groups such as thienyl,furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromaticheterocyclic groups such as benzothiophenyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl,furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl,thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl,thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl,pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl,isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

In the present specification, examples of the “non-aromatic heterocyclicgroup” (including “3- to 14-membered non-aromatic heterocyclic group”)include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom.

Preferable examples of the “non-aromatic heterocyclic group” include 3-to 8-membered monocyclic non-aromatic heterocyclic groups such asaziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl,tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl,pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl,tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl,azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and thelike; and 9- to 14-membered fused polycyclic (preferably bi ortricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl,dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl,dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl,isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl,tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl,tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl,tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl andthe like.

In the present specification, preferable examples of the “7- to10-membered bridged heterocyclic group” include quinuclidinyl and7-azabicyclo[2.2.1]heptanyl.

In the present specification, examples of the “nitrogen-containingheterocyclic group” include a “heterocyclic group” containing at leastone nitrogen atom as a ring-constituting atom.

In the present specification, examples of the “optionally substitutedheterocyclic group” include a heterocyclic group optionally havingsubstituent(s) selected from the aforementioned substituent group A.

The number of the substituents in the “optionally substitutedheterocyclic group” is, for example, 1 to 3. When the number of thesubstituents is two or more, the respective substituents may be the sameor different.

In the present specification, examples of the “acyl group” include aformyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group,a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group,each optionally having “1 or 2 substituents selected from a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₃₋₁₀ cycloalkyl group, a C₃₋₁₀cycloalkenyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, a 5- to14-membered aromatic heterocyclic group and a 3- to 14-memberednon-aromatic heterocyclic group, each of which optionally has 1 to 3substituents selected from a halogen atom, an optionally halogenatedC₁₋₆ alkoxy group, a hydroxy group, a nitro group, a cyano group, anamino group and a carbamoyl group”.

Examples of the “acyl group” also include a hydrocarbon-sulfonyl group,a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and aheterocyclylsulfinyl group.

Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bondedsulfonyl group, the heterocyclylsulfonyl group means a heterocyclicgroup-bonded sulfonyl group, the hydrocarbon-sulfinyl group means ahydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinylgroup means a heterocyclic group-bonded sulfinyl group.

Preferable examples of the “acyl group” include a formyl group, acarboxy group, a C₁₋₆ alkyl-carbonyl group, a C₂₋₆ alkenyl-carbonylgroup (e.g., crotonoyl), a C₃₋₁₀ cycloalkylcarbonyl group (e.g.,cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,cycloheptanecarbonyl), a C₃₋₁₀ cycloalkenyl-carbonyl group (e.g.,2-cyclohexenecarbonyl), a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a C₆₋₁₄ aryloxy-carbonyl group (e.g.,phenyloxycarbonyl, naphthyloxycarbonyl), a C₇₋₁₆ aralkyloxy-carbonylgroup (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoylgroup, a mono- or di-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₂₋₆alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), a mono- ordi-C₆₋₁₄ aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- ordi-C₇₋₁₆ aralkyl-carbamoyl group, a 5- to 14-membered aromaticheterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a thiocarbamoylgroup, a mono- or di-C₁₋₆ alkyl-thiocarbamoyl group (e.g.,methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- ordi-C₃₋₁₀ cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to14-membered aromatic heterocyclylthiocarbamoyl group (e.g.,pyridylthiocarbamoyl), a sulfino group, a C₁₋₆ alkylsulfinyl group(e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C₁₋₆alkylsulfonyl group, a C₆₋ ₁₄ arylsulfonyl group, a phosphono group anda mono- or di-C₁₋₆ alkylphosphono group (e.g., dimethylphosphono,diethylphosphono, diisopropylphosphono, dibutylphosphono).

In the present specification, examples of the “optionally substitutedamino group” include an amino group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted amino group include anamino group, a mono- or di-(optionally halogenated C₁₋₆ alkyl)aminogroup (e.g., methylamino, trifluoromethylamino, dimethylamino,ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C₂₋₆alkenylamino group (e.g., diallylamino), a mono- or di-C₃₋₁₀cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono-or di-C₆₋₁₄ arylamino group (e.g., phenylamino), a mono- or di-C₇₋₁₆aralkylamino group (e.g., benzylamino, dibenzylamino), a mono-ordi-(optionally halogenated C₁₋₆ alkyl)-carbonylamino group (e.g.,acetylamino, propionylamino), a mono- or di-C₆₋₁₄ aryl-carbonylaminogroup (e.g., benzoylamino), a mono- or di-C₇₋₁₆ aralkyl-carbonylaminogroup (e.g., benzylcarbonylamino), a mono- or di-5- to 14-memberedaromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,isonicotinoylamino), a mono- or di-3- to 14-membered non-aromaticheterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), amono- or di-C₁₋₆ alkoxy-carbonylamino group (e.g.,tert-butoxycarbonylamino), a 5- to 14-membered aromaticheterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a(mono- or di-C₁₋₆ alkyl-carbamoyl)amino group (e.g.,methylcarbamoylamino), a (mono- or di-C₇₋₁₆ aralkyl-carbamoyl) aminogroup (e.g., benzylcarbamoylamino), a C₁₋₆ alkylsulfonylamino group(e.g., methylsulfonylamino, ethylsulfonylamino), a C₆₋₁₄arylsulfonylamino group (e.g., phenylsulfonylamino), a (C₁₋₆ alkyl)(C₁₋₆alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino) and a (C₁₋₆alkyl) (C₆₋₁₄ aryl-carbonyl) amino group (e.g.,N-benzoyl-N-methylamino).

In the present specification, examples of the “optionally substitutedcarbamoyl group” include a carbamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋ ₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, each of which optionally has1 to 3 substituents selected from substituent group A”.

Preferable examples of the optionally substituted carbamoyl groupinclude a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group, amono- or di-C₂₋₆ alkenyl-carbamoyl group (e.g., diallylcarbamoyl), amono- or di-C₃₋₁₀ cycloalkyl-carbamoyl group (e.g.,cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C₇₋₁₆aralkyl-carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbonyl-carbamoylgroup (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C₆₋₁₄aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to14-membered aromatic heterocyclylcarbamoyl group (e.g.,pyridylcarbamoyl).

In the present specification, examples of the “optionally substitutedthiocarbamoyl group” include a thiocarbamoyl group optionally having “1or 2 substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenylgroup, a C₃₋₁₀ cycloalkyl group, a C₆₋ ₁₄ aryl group, a C₇₋₁₆ aralkylgroup, a C₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, each of which optionally has1 to 3 substituents selected from substituent group A”.

Preferable examples of the optionally substituted thiocarbamoyl groupinclude a thiocarbamoyl group, a mono- or di-C₁₋₆ alkyl-thiocarbamoylgroup (e.g., methylthiocarbamoyl, ethylthiocarbamoyl,dimethylthiocarbamoyl, diethylthiocarbamoyl,N-ethyl-N-methylthiocarbamoyl), a mono- or di-C₂₋₆ alkenyl-thiocarbamoylgroup (e.g., diallylthiocarbamoyl), a mono- or di-C₃₋₁₀cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,cyclohexylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-thiocarbamoyl group(e.g., phenylthiocarbamoyl), a mono- or di-C₇₋₁₆ aralkyl-thiocarbamoylgroup (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- ordi-C₁₋₆ alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl,propionylthiocarbamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-thiocarbamoylgroup (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromaticheterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

In the present specification, examples of the “optionally substitutedsulfamoyl group” include a sulfamoyl group optionally having “1 or 2substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋ ₁₄ aryl group, a C₇₋₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5-to 14-membered aromatic heterocyclylcarbonylgroup, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, aC₁₋₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclicgroup, a carbamoyl group, a mono- or di-C₁₋₆ alkyl-carbamoyl group and amono- or di-C₇₋₁₆ aralkyl-carbamoyl group, each of which optionally has1 to 3 substituents selected from substituent group A”.

Preferable examples of the optionally substituted sulfamoyl groupinclude a sulfamoyl group, a mono- or di-C₁₋₆ alkyl-sulfamoyl group(e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl,diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C₂₋₆alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C₃₋₁₀cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl,cyclohexylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-sulfamoyl group (e.g.,phenylsulfamoyl), a mono- or di-C₇₋₁₆ aralkyl-sulfamoyl group (e.g.,benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C₁₋₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,propionylsulfamoyl), a mono- or di-C₆₋₁₄ aryl-carbonyl-sulfamoyl group(e.g., benzoylsulfamoyl) and a 5- to 14-membered aromaticheterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

In the present specification, examples of the “optionally substitutedhydroxy group” include a hydroxyl group optionally having “a substituentselected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₃₋₁₀cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋ ₁₆ aralkyl group, a C₁₋₆alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group, a C₇₋₁₆aralkyl-carbonyl group, a 5- to 14-membered aromaticheterocyclylcarbonyl group, a 3- to 14-membered non-aromaticheterocyclylcarbonyl group, a C₁₋₆ alkoxy-carbonyl group, a 5- to14-membered aromatic heterocyclic group, a carbamoyl group, a mono- ordi-C₁₋₆ alkyl-carbamoyl group, a mono- or di-C₇₋₁₆ aralkyl-carbamoylgroup, a C₁₋₆ alkylsulfonyl group and a C₆₋₁₄ arylsulfonyl group, eachof which optionally has 1 to 3 substituents selected from substituentgroup A”.

Preferable examples of the optionally substituted hydroxy group includea hydroxy group, a C₁₋₆ alkoxy group, a C₂₋₆ alkenyloxy group (e.g.,allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C₃₋₁₀cycloalkyloxy group (e.g., cyclohexyloxy), a C₆₋₁₄ aryloxy group (e.g.,phenoxy, naphthyloxy), a C₇₋₁₆ aralkyloxy group (e.g., benzyloxy,phenethyloxy), a C₁₋₆ alkyl-carbonyloxy group (e.g., acetyloxy,propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C₆₋₁₄aryl-carbonyloxy group (e.g., benzoyloxy), a C₇₋₁₆ aralkyl-carbonyloxygroup (e.g., benzylcarbonyloxy), a 5- to 14-membered aromaticheterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-memberednon-aromatic heterocyclylcarbonyloxy group (e.g.,piperidinylcarbonyloxy), a C₁₋₆ alkoxy-carbonyloxy group (e.g.,tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxygroup (e.g., pyridyloxy), a carbamoyloxy group, a C₁₋₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C₇₋₁₆aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C₁₋₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and aC₆₋₁₄ arylsulfonyloxy group (e.g., phenylsulfonyloxy).

In the present specification, examples of the “optionally substitutedsulfanyl group” include a sulfanyl group optionally having “asubstituent selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group, a C₇₋ ₁₆ aralkyl group, aC₁₋₆ alkyl-carbonyl group, a C₆₋₁₄ aryl-carbonyl group and a 5- to14-membered aromatic heterocyclic group, each of which optionally has 1to 3 substituents selected from substituent group A” and a halogenatedsulfanyl group.

Preferable examples of the optionally substituted sulfanyl group includea sulfanyl (-SH) group, a C₁₋₆ alkylthio group, a C₂₋₆ alkenylthio group(e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C₃₋₁₀cycloalkylthio group (e.g., cyclohexylthio), a C₆₋₁₄ arylthio group(e.g., phenylthio, naphthylthio), a C₇₋₁₆ aralkylthio group (e.g.,benzylthio, phenethylthio), a C₁₋₆ alkyl-carbonylthio group (e.g.,acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), aC₆₋₁₄ aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-memberedaromatic heterocyclylthio group (e.g., pyridylthio) and a halogenatedthio group (e.g., pentafluorothio).

In the present specification, examples of the “optionally substitutedsilyl group” include a silyl group optionally having “1 to 3substituents selected from a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, aC₃₋₁₀ cycloalkyl group, a C₆₋₁₄ aryl group and a C₇₋₁₆ aralkyl group,each of which optionally has 1 to 3 substituents selected fromsubstituent group A”.

Preferable examples of the optionally substituted silyl group include atri-C₁₋₆ alkylsilyl group (e.g., trimethylsilyl,tert-butyl(dimethyl)silyl).

In the present specification, examples of the “hydrocarbon ring” includea C₆₋₁₄ aromatic hydrocarbon ring, C₃₋ ₁₀ cycloalkane and C₃₋₁₀cycloalkene.

In the present specification, examples of the “C₆₋₁₄ aromatichydrocarbon ring” include benzene and naphthalene.

In the present specification, examples of the “C₃₋₁₀ cycloalkane”include cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane and cyclooctane.

In the present specification, examples of the “C₃₋₁₀ cycloalkene”include cyclopropene, cyclobutene, cyclopentene, cyclohexene,cycloheptene and cyclooctene.

In the present specification, examples of the “heterocyclic group”include an aromatic heterocyclic group and a non-aromatic heterocyclicgroup, each containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom.

In the present specification, examples of the “aromatic heterocyclicgroup” include a 5- to 14-membered (preferably 5-to 10-membered)aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfuratom and an oxygen atom. Preferable examples of the “aromaticheterocycle” include 5- or 6-membered monocyclic aromatic heterocyclessuch as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole,isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine,pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, triazole, tetrazole, triazine and the like; and 8- to14-membered fused polycycle (preferably bi or tricyclic) aromaticheterocycles such as benzothiophene, benzofuran, benzimidazole,benzoxazole, benzisoxazole, benzothiazole, benzisothiazole,benzotriazole, imidazopyridine, thienopyridine, furopyridine,pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine,imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine,pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine,thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine,naphtho[2,3-b]thiophene, phenoxathiine, indole, isoindole, 1H-indazole,purine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, carbazole, β-carboline,phenanthridine, acridine, phenazine, phenothiazine, phenoxathiine andthe like.

In the present specification, examples of the “non-aromatic heterocycle”include a 3- to 14-membered (preferably 4- to 10-membered) non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom. Preferable examples of the “non-aromatic heterocycle”include 3- to 8-membered monocyclic non-aromatic heterocyclic groupssuch as aziridine, oxirane, thiirane, azetidine, oxetane, thietane,tetrahydrothiophene, tetrahydrofuran, Pyrroline, pyrrolidine,imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,tetrahydropyridine, dihydropyridine, dihydrothiopyran,tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,azepanine, diazepane, azepine, azocane, diazocane, oxepane and the like;and 9- to 14-membered fused polycyclic (preferably bi or tricyclic)non-aromatic heterocycles such as dihydrobenzofuran,dihydrobenzoimidazole, dihydrobenzooxazole, dihydrobenzothiazole,dihydrobenzoisothiazole, dihydronaphto[2,3-b]thiophene,tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline,isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzoazepine,tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine,hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine,tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole,tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine,tetrahydrothioxanthene, octahydroisoquinoline and the like.

In the present specification, examples of the “nitrogen-containingheterocycle” include the “heterocycle” containing at least one nitrogenatom as a ring-constituting atom.

In the present specification, examples of the “C₃₋₁₀ cycloalkyl group”also include bicyclo[1.1.1]pentyl.

Each symbol in the formula (I) is explained below.

X¹ is CH or N.

In one embodiment of the present invention, X¹ is preferably CH.

In another embodiment of the present invention, X¹ is preferably N.

X² is CR¹⁰ or N, and R¹⁰ is a hydrogen atom or a halogen atom.

In one embodiment of the present invention, X² is preferably CR¹⁰.

In another embodiment of the present invention, X² is preferably N.

As the halogen atom for R¹⁰, a fluorine atom, a chlorine atom and abromine atom can be mentioned, with preference given to a fluorine atom.

In one embodiment of the present invention, R¹⁰ is preferably a hydrogenatom or a fluorine atom.

In another embodiment of the present invention, R¹⁰ is preferably ahalogen atom, more preferably a fluorine atom.

R¹ and R² are each independently a hydrogen atom, a halogen atom, anoptionally substituted C₁₋₆ alkyl group, or an optionally substitutedC₁₋₆ alkoxy group.

R¹ is preferably a hydrogen atom, a halogen atom (e.g., chlorine atom,fluorine atom), a C₁₋₆ alkyl group (e.g., methyl), or a C₁₋₆ alkoxygroup (e.g., methoxy), more preferably, a hydrogen atom, a halogen atom(e.g., chlorine atom, fluorine atom), or a C₁₋₆ alkyl group (e.g.,methyl), further preferably a halogen atom (e.g., chlorine atom) or aC₁₋₆ alkyl group (e.g., methyl).

R² is preferably a hydrogen atom, a halogen atom (e.g., chlorine atom,fluorine atom), a C₁₋₆ alkyl group (e.g., methyl), or a C₁₋₆ alkoxygroup (e.g., methoxy), more preferably a C₁₋₆ alkyl group (e.g., methyl)or a C₁₋₆ alkoxy group (e.g., methoxy), further preferably a C₁₋₆ alkylgroup (e.g., methyl).

In a preferable embodiment of the present invention, when one of R¹ andR² is a hydrogen atom, the other is other than a hydrogen atom.

In one embodiment of the present invention, R¹ is a C₁₋₆ alkyl group(e.g., methyl) or a halogen atom (e.g., chlorine atom, fluorine atom),and R² is a C₁₋₆ alkyl group (e.g., methyl).

In another embodiment of the present invention, R¹ is a hydrogen atomand R² is a C₁₋₆ alkoxy group (e.g., methoxy).

R³ and R⁴ are each independently a hydrogen atom, a halogen atom, ahydroxy group, an optionally substituted C₁₋₆ alkyl group, or anoptionally substituted C₁₋₆ alkoxy group.

Preferably, R³ and R⁴ are each independently a hydrogen atom, a halogenatom, a hydroxy group, a C₁₋₆ alkyl group or a C₁₋₆ alkoxy group,further preferably a hydrogen atom.

R⁵ and R⁶ are each independently a hydrogen atom or a halogen atom.

Examples of the halogen atom for R⁵ or R⁶ include a fluorine atom, achlorine atom and a bromine atom.

In one embodiment of the present invention, R⁵ and R⁶ are eachpreferably a hydrogen atom.

In another embodiment of the present invention, R⁵ is a hydrogen atom,and R⁶ is a hydrogen atom or a halogen atom (e.g., fluorine atom).

R⁷ is a substituted monocyclic heterocyclic group, an optionallysubstituted carbamoyl group, an optionally substituted C₁₋₆ alkyl group,a carboxy group, a substituted C₁₋₆ alkoxy group, an optionallysubstituted heteroaryloxy group, or a group represented by N(R⁸)COR⁹wherein R⁸ is a hydrogen atom or an optionally substituted C₁₋₆ alkylgroup and R⁹ is an optionally substituted C₁₋₆ alkyl group.

As the “monocyclic heterocyclic group” of the “substituted monocyclicheterocyclic group” for R⁷, a 5- or 6-membered monocyclic aromaticheterocyclic group, a 3- to 8-membered monocyclic non-aromaticheterocyclic group and the like can be mentioned.

As the “5- or 6-membered monocyclic aromatic heterocyclic group”exemplified as the aforementioned “monocyclic heterocyclic group”, a 5-or 6-membered monocyclic aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom can be mentioned.Specifically, those similar to the examples recited as the “5- or6-membered monocyclic aromatic heterocyclic group” from among thepreferable examples of the aforementioned “aromatic heterocyclic group”can be mentioned.

As the “3- or 8-membered monocyclic non-aromatic heterocyclic group”exemplified as the aforementioned “monocyclic heterocyclic group”, a 3-or 8-membered monocyclic non-aromatic heterocyclic group containing, asa ring-constituting atom besides carbon atom, 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom can bementioned. Specifically, those similar to the examples recited as the“3- or 8-membered monocyclic non-aromatic heterocyclic group” from amongthe preferable examples of the aforementioned “non-aromatic heterocyclicgroup” can be mentioned.

As the “monocyclic heterocyclic group”, a 5- or 6-membered monocyclicaromatic heterocyclic group (e.g., pyrazolyl, triazolyl, imidazolyl,pyridazinyl) and a 3- to 8-membered monocyclic non-aromatic heterocyclicgroup (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl) can bementioned. Preferably, a 5- or 6-membered monocyclic aromaticheterocyclic group (e.g., pyrazolyl, triazolyl, imidazolyl, pyridazinyl)can be mentioned, and further preferably, pyrazolyl and triazolyl can bementioned.

The “monocyclic heterocyclic group” of the “substituted monocyclicheterocyclic group” for R⁷ optionally has 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of such substituentinclude the aforementioned “substituent” and an oxo group. When pluralsubstituents are present, the respective substituents may be the same ordifferent.

As the substituent of the “substituted monocyclic heterocyclic group”for R⁷, an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₃₋₁₀ cycloalkyl group, an optionally substitutedheterocyclic group, an oxo group and the like can be mentioned.

The “substituted monocyclic heterocyclic group” for R⁷ is preferably a5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,pyrazolyl, triazolyl, imidazolyl, pyridazinyl) substituted by 1 to 3(preferably 1 or 2) substituents selected from

-   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, tert-butyl) optionally    substituted by 1 to 3 substituents selected from a halogen atom    (e.g., fluorine atom), a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl),    a C₁₋₆ alkoxy group (e.g., methoxy), and a mono- or di-C₁₋₆    alkyl-carbamoyl group (e.g., dimethylcarbamoyl),-   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and-   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic group    (e.g., tetrahydropyranyl).

As the “optionally substituted carbamoyl group” for R⁷, theaforementioned “optionally substituted carbamoyl group” can bementioned.

The two substituents that the “carbamoyl group” of the “optionallysubstituted carbamoyl group” has may form an optionally substituted ringtogether with the adjacent nitrogen atom. As such ring, azetidine,pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,azepane, diazepane, azocane, diazocane, oxazepane and the like can bementioned. The ring optionally has 1 to 5 (preferably 1 to 3)substituents at substitutable position(s). Examples of such substituentinclude the aforementioned “substituent”. When plural substituents arepresent, the respective substituents may be the same or different.

Specifically, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl,piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl,thiomorpholin-4-ylcarbonyl, azepan-1-ylcarbonyl,1,4-diazepan-1-ylcarbonyl, azocan-1-ylcarbonyl,1,5-diazocan-1-ylcarbonyl, 1,4-oxazepan-4-ylcarbonyl and the like, eachof which is optionally substituted, can be mentioned. Preferred isazetidin-1-ylcarbonyl. Examples of the substituent on the ring include 1to 3 substituents selected from an optionally halogenated C₁₋₆ alkylgroup, a hydroxy group, a C₁₋₆ alkoxy group and the like.

The “optionally substituted carbamoyl group” for R⁷ is preferably

-   (1) a carbamoyl group optionally substituted by 1 or 2    (preferably 1) substituents selected from    -   (a) an optionally substituted C₁₋₆ alkyl group,    -   (b) an optionally substituted C₃₋₁₀ cycloalkyl group, and    -   (c) an optionally substituted heterocyclic group, or-   (2) an optionally substituted azetidin-1-ylcarbonyl group.

The “optionally substituted carbamoyl group” for R⁷ is more preferably

-   (1) a carbamoyl group substituted by 1 or 2 (preferably 1)    substituents selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,        isobutyl, tert-butyl) optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom (e.g., fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl) optionally            substituted by 1 to 3 (preferably 1) hydroxy groups,        -   (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,            dimethylcarbamoyl),        -   (iv) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),        -   (v) a hydroxy group,        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl, tetrahydrofuranyl, pyrrolidinyl,            tetrahydropyranyl, morpholinyl) optionally substituted by            one oxo group, and        -   (vii) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        bicyclo[1.1.1]pentyl) optionally substituted by 1 to 3        (preferably 1 or 2) substituents selected from a halogen atom        (e.g., fluorine atom), an optionally halogenated C₁₋₆ alkyl        group (e.g., methyl, difluoromethyl) and a cyano group, and    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., oxetanyl, thietanyl, tetrahydrofuranyl,        tetrahydropyranyl) optionally substituted by 1 to 3 (preferably        1 or 2) substituents selected from a C₁₋₆ alkyl group (e.g.,        methyl), an oxo group and a hydroxy group, or-   (2) an azetidin-1-ylcarbonyl group optionally substituted by 1 to 3    (preferably 1) substituents selected from an optionally halogenated    C₁₋₆ alkyl group (e.g., difluoromethyl), a hydroxy group and a C₁₋₆    alkoxy group (e.g., methoxy).

The “C₁₋₆ alkyl group” of the “optionally substituted C₁₋₆ alkyl group”for R⁷ optionally has 1 to 5 (preferably 1 to 3) substituents atsubstitutable position(s). Examples of such substituent include theaforementioned “substituent”. When plural substituents are present, therespective substituents may be the same or different.

The “optionally substituted C₁₋₆ alkyl group” for R⁷ is preferably aC₁₋₆ alkyl group.

The “C₁₋₆ alkoxy group” of the “substituted C₁₋₆ alkoxy group” for R⁷optionally has 1 to 5 (preferably 1 to 3) substituents at substitutableposition(s). Examples of such substituent include the aforementioned“substituent”. When plural substituents are present, the respectivesubstituents may be the same or different.

The “substituted C₁₋₆ alkoxy group” for R⁷ is preferably a C₁₋₆ alkoxygroup substituted by 1 to 3 substituents selected from a halogen atom, ahydroxy group, a C₁₋₆ alkoxy group and the like.

As the “heteroaryloxy group” of the “optionally substitutedheteroaryloxy group” for R⁷, a heteroaryloxy group wherein theheteroaryl moiety is the aforementioned “aromatic heterocyclic group”can be mentioned. Examples of the heteroaryl moiety include thosesimilar to the examples recited for the aforementioned “aromaticheterocyclic group”.

The “heteroaryloxy group” of the “optionally substituted heteroaryloxygroup” for R⁷ optionally has 1 to 5 (preferably 1 to 3) substituents atsubstitutable position(s). Examples of such substituent include theaforementioned “substituent”. When plural substituents are present, therespective substituents may be the same or different.

When R⁷ is a group represented by N(R⁸)COR⁹, R⁸ is a hydrogen atom or anoptionally substituted C₁₋₆ alkyl group, and R⁹ is an optionallysubstituted C₁₋₆ alkyl group.

The “C₁₋₆ alkyl group” of the “optionally substituted C₁₋₆ alkyl group”for R⁸ or R⁹ optionally has 1 to 5 (preferably 1 to 3) substituents atsubstitutable position(s). Examples of such substituent include theaforementioned “substituent”. When plural substituents are present, therespective substituents may be the same or different.

The “optionally substituted C₁₋₆ alkyl group” for R⁸ or R⁹ is preferablya C₁₋₆ alkyl group.

R⁷ is preferably

-   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    pyrazolyl, triazolyl, imidazolyl, pyridazinyl) substituted by 1 to 3    (preferably 1 or 2) substituents selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, tert-butyl)        optionally substituted by 1 to 3 substituents selected from a        halogen atom (e.g., fluorine atom), a C₃₋₁₀ cycloalkyl group        (e.g., cyclopropyl), a C₁₋₆ alkoxy group (e.g., methoxy), and a        mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,        dimethylcarbamoyl),    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl),-   (2) a carbamoyl group substituted by 1 or 2 (preferably 1)    substituents selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,        isobutyl, tert-butyl) optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom (e.g., fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl) optionally            substituted by 1 to 3 (preferably 1) hydroxy groups,        -   (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,            dimethylcarbamoyl),        -   (iv) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),        -   (v) a hydroxy group,        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl, tetrahydrofuranyl, pyrrolidinyl,            tetrahydropyranyl, morpholinyl) optionally substituted by            one oxo group, and        -   (vii) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        bicyclo[1.1.1]pentyl) optionally substituted by 1 to 3        (preferably 1 or 2) substituents selected from a halogen atom        (e.g., fluorine atom), an optionally halogenated C₁₋₆ alkyl        group (e.g., methyl, difluoromethyl) and a cyano group, and    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., oxetanyl, thietanyl, tetrahydrofuranyl,        tetrahydropyranyl) optionally substituted by 1 to 3 (preferably        1 or 2) substituents selected from a C₁₋₆ alkyl group (e.g.,        methyl), an oxo group and a hydroxy group,-   (3) an azetidin-1-ylcarbonyl group optionally substituted by 1 to 3    (preferably 1) substituents selected from an optionally halogenated    C₁₋₆ alkyl group (e.g., difluoromethyl), a hydroxy group and a C₁₋₆    alkoxy group (e.g., methoxy)-   (4) a C₁₋₆ alkyl group (e.g., methyl), or-   (5) a carboxy group.

R⁷ is more preferably,

-   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    pyrazolyl, triazolyl, imidazolyl, pyridazinyl) substituted by 1 to 3    (preferably 1 or 2) substituents selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally        substituted by 1 to 3 (preferably 1) substituents selected from        a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl) and a C₁₋₆ alkoxy        group (e.g., methoxy),    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl),-   (2) a carbamoyl group substituted by 1 or 2 (preferably 1)    substituents selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isobutyl)        optionally substituted by 1 to 3 substituents selected from        -   (i) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl) optionally            substituted by 1 to 3 (preferably 1) hydroxy groups,        -   (ii) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,            dimethylcarbamoyl),        -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),        -   (iv) a hydroxy group,        -   (v) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl, tetrahydrofuranyl, pyrrolidinyl)            optionally substituted by one oxo group, and        -   (vi) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)        optionally substituted by 1 to 3 (preferably 1 or 2) halogen        atoms (e.g., fluorine atom), and    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., oxetanyl, thietanyl, tetrahydrofuranyl) optionally        substituted by 1 to 3 (preferably 1 or 2) substituents selected        from a C₁₋₆ alkyl group (e.g., methyl) and an oxo group, or (3)        an azetidin-1-ylcarbonyl group optionally substituted by 1 to 3        (preferably 1) C₁₋₆ alkoxy groups (e.g., methoxy).

R⁷ is further preferably,

-   (1) a pyrazolyl group or a triazolyl group each substituted by 1 or    2 substituents selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, tert-butyl)        optionally substituted by 1 to 3 substituents selected from a        halogen atom (e.g., fluorine atom), a C₃₋₁₀ cycloalkyl group        (e.g., cyclopropyl), and a C₁₋₆ alkoxy group (e.g., methoxy),        and    -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl), or-   (2) a carbamoyl group substituted by one substituent selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl) optionally        substituted by 1 to 3 (preferably 1) substituents selected from        a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy) and a 3- to        8-membered monocyclic non-aromatic heterocyclic group (e.g.,        tetrahydrofuranyl), and    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl).

R⁷ is furthermore preferably

-   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g.,    triazolyl, pyrazolyl) substituted by 1 to 3 C₁₋₆ alkyl groups, or-   (2) a carbamoyl group substituted by a C₁₋₆ alkyl group optionally    substituted by one substituent selected from a C₁₋₆ alkoxy group and    a 3- to 8-membered monocyclic non-aromatic heterocyclic group (e.g.,    tetrahydrofuranyl).

In one embodiment of the present invention, compound (I) is preferably acompound having a steric structure represented by the formula (I)-1, ora salt thereof.

wherein each symbol is as defined above.

As preferable embodiments of compound (I), the following compounds canbe mentioned.

Compound I-1

Compound (I) wherein

-   X¹ is a CH or N;-   X² is a CR¹⁰ or N;-   R¹⁰ is a hydrogen atom or a halogen atom (e.g., fluorine atom);-   R¹ and R² are each independently a hydrogen atom, a halogen atom    (e.g., chlorine atom, fluorine atom), a C₁₋₆ alkyl group (e.g.,    methyl) or a C₁₋₆ alkoxy group (e.g., methoxy);-   R³ and R⁴ are each independently a hydrogen atom or a halogen atom    (e.g., fluorine atom);-   R⁵ and R⁶ are each a hydrogen atom; and-   R⁷ is    -   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl, triazolyl, imidazolyl, pyridazinyl)        substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, tert-butyl)            optionally substituted by 1 to 3 substituents selected from            a halogen atom (e.g., fluorine atom), a C₃₋₁₀ cycloalkyl            group (e.g., cyclopropyl), a C₁₋₆ alkoxy group (e.g.,            methoxy), and a mono- or di-C₁₋₆ alkyl-carbamoyl group            (e.g., dimethylcarbamoyl),        -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., tetrahydropyranyl),    -   (2) a carbamoyl group substituted by 1 or 2 (preferably 1)        substituents selected from        -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl,            isopropyl, isobutyl, tert-butyl) optionally substituted by 1            to 3 substituents selected from            -   (i) a halogen atom (e.g., fluorine atom),            -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl)                optionally substituted by 1 to 3 hydroxy groups,            -   (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,                dimethylcarbamoyl),            -   (iv) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),            -   (v) a hydroxy group,            -   (vi) a 3- to 8-membered monocyclic non-aromatic                heterocyclic group (e.g., oxetanyl, tetrahydrofuranyl,                pyrrolidinyl, tetrahydropyranyl, morpholinyl) optionally                substituted by one oxo group, and            -   (vii) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),        -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,            bicyclo[1.1.1]pentyl) optionally substituted by 1 to 3            substituents selected from a halogen atom (e.g., fluorine            atom), an optionally halogenated C₁₋₆ alkyl group (e.g.,            methyl, difluoromethyl), and a cyano group, and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl, thietanyl, tetrahydrofuranyl,            tetrahydropyranyl) optionally substituted by 1 to 3            substituents selected from a C₁₋₆ alkyl group (e.g.,            methyl), an oxo group and a hydroxy group,    -   (3) an azetidin-1-ylcarbonyl group optionally substituted by 1        to 3 substituents selected from an optionally halogenated C₁₋₆        alkyl group (e.g., difluoromethyl), a hydroxy group and a C₁₋₆        alkoxy group (e.g., methoxy),    -   (4) a C₁₋₆ alkyl group (e.g., methyl), or    -   (5) a carboxy group.

Compound I-2

Compound (I) wherein

-   X¹ is a CH or N;-   X² is a CR¹⁰ or N;-   R¹⁰ is a hydrogen atom or a halogen atom (e.g., fluorine atom);-   R¹ and R² are each independently a hydrogen atom, a halogen atom    (e.g., chlorine atom, fluorine atom), a C₁₋₆ alkyl group (e.g.,    methyl) or a C₁₋₆ alkoxy group (e.g., methoxy);-   R³ and R⁴ are each a hydrogen atom;-   R⁵ and R⁶ are each a hydrogen atom; and-   R⁷ is    -   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl, triazolyl, imidazolyl, pyridazinyl)        substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, tert-butyl)            optionally substituted by 1 to 3 substituents selected from            a halogen atom (e.g., fluorine atom), a C₃₋₁₀ cycloalkyl            group (e.g., cyclopropyl), a C₁₋₆ alkoxy group (e.g.,            methoxy), and a mono- or di-C₁₋₆ alkyl-carbamoyl group            (e.g., dimethylcarbamoyl),        -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., tetrahydropyranyl),    -   (2) a carbamoyl group substituted by 1 or 2 (preferably 1)        substituents selected from        -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl,            isopropyl, isobutyl, tert-butyl) optionally substituted by 1            to 3 substituents selected from            -   (i) a halogen atom (e.g., fluorine atom),            -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl)                optionally substituted by 1 to 3 hydroxy groups,            -   (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,                dimethylcarbamoyl),            -   (iv) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),            -   (v) a hydroxy group,            -   (vi) a 3- to 8-membered monocyclic non-aromatic                heterocyclic group (e.g., oxetanyl, tetrahydrofuranyl,                pyrrolidinyl, tetrahydropyranyl, morpholinyl) optionally                substituted by one oxo group, and            -   (vii) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),        -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,            bicyclo[1.1.1]pentyl) optionally substituted by 1 to 3            substituents selected from a halogen atom (e.g., fluorine            atom), an optionally halogenated C₁₋₆ alkyl group (e.g.,            methyl, difluoromethyl), and a cyano group, and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl, thietanyl, tetrahydrofuranyl,            tetrahydropyranyl) optionally substituted by 1 to 3            substituents selected from a C₁₋₆ alkyl group (e.g.,            methyl), an oxo group and a hydroxy group,    -   (3) an azetidin-1-ylcarbonyl group optionally substituted by 1        to 3 substituents selected from an optionally halogenated C₁₋₆        alkyl group (e.g., difluoromethyl), a hydroxy group and a C₁₋₆        alkoxy group (e.g., methoxy),    -   (4) a C₁₋₆ alkyl group (e.g., methyl), or    -   (5) a carboxy group.

Compound I-3

Compound (I) wherein

-   X¹ is a CH or N;-   X² is a CR¹⁰ or N;-   R¹⁰ is a hydrogen atom or a halogen atom (e.g., fluorine atom);-   R¹ and R² are each independently a hydrogen atom, a halogen atom    (e.g., chlorine atom, fluorine atom), a C₁₋₆ alkyl group (e.g.,    methyl), or a C₁₋₆ alkoxy group (e.g., methoxy);-   R³ and R⁴ are each a hydrogen atom;-   R⁵ and R⁶ are each a hydrogen atom; and-   R⁷ is    -   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl, triazolyl, imidazolyl, pyridazinyl)        substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl) optionally            substituted by 1 to 3 substituents selected from a C₃₋₁₀            cycloalkyl group (e.g., cyclopropyl) and a C₁₋₆ alkoxy group            (e.g., methoxy),        -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., tetrahydropyranyl),    -   (2) a carbamoyl group substituted by 1 or 2 (preferably 1)        substituents selected from        -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl,            isobutyl) optionally substituted by 1 to 3 substituents            selected from            -   (i) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl)                optionally substituted by 1 to 3 hydroxy groups,            -   (ii) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,                dimethylcarbamoyl),            -   (iii) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),            -   (iv) a hydroxy group,            -   (v) a 3- to 8-membered monocyclic non-aromatic                heterocyclic group (e.g., oxetanyl, tetrahydrofuranyl,                pyrrolidinyl) optionally substituted by one oxo group,                and            -   (vi) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),        -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl)            optionally substituted by 1 to 3 halogen atoms (e.g.,            fluorine atom), and        -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl, thietanyl, tetrahydrofuranyl)            optionally substituted by 1 to 3 substituents selected from            an C₁₋₆ alkyl group (e.g., methyl) and an oxo group, or

        (3) an azetidin-1-ylcarbonyl group optionally substituted by 1        to 3 C₁₋₆ alkoxy groups (e.g., methoxy).

Compound I-4

Compound (I) wherein

-   X¹ is a CH or N;-   X² is a CR¹⁰ or N;-   R¹⁰ is a hydrogen atom or a halogen atom (e.g., fluorine atom);-   R¹ and R² are each independently a halogen atom (e.g., chlorine    atom) or a C₁₋₆ alkyl group (e.g., methyl);-   R³ and R⁴ are each a hydrogen atom;-   R⁵ and R⁶ are each a hydrogen atom; and-   R⁷ is    -   (1) a pyrazolyl group or a triazolyl group each substituted by 1        or 2 substituents selected from        -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, tert-butyl)            optionally substituted by 1 to 3 substituents selected from            a halogen atom (e.g., fluorine atom), a C₃₋₁₀ cycloalkyl            group (e.g., cyclopropyl), and a C₁₋₆ alkoxy group (e.g.,            methoxy), and        -   (b) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., tetrahydropyranyl), or    -   (2) a carbamoyl group substituted by one substituent selected        from        -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl)            optionally substituted by 1 to 3 (preferably 1) substituents            selected from a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy)            and a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., tetrahydrofuranyl), and        -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl).

Compound I-5

The aforementioned [Compound I-2] wherein X¹ is CH.

Compound I-6

Compound (I) wherein

-   X¹ is N;-   X² is CR¹⁰ or N;-   R¹⁰ is a hydrogen atom or a halogen atom (e.g., fluorine atom);-   R¹ and R² are each independently a halogen atom (e.g., chlorine    atom) or a C₁₋₆ alkyl group (e.g., methyl);-   R³ and R⁴ are each a hydrogen atom;-   R⁵ and R⁶ are each a hydrogen atom; and-   R⁷ is    -   (1) a 5- or 6-membered monocyclic aromatic heterocyclic group        (e.g., pyrazolyl, triazolyl) substituted by 1 to 3 C₁₋₆ alkyl        groups (e.g., methyl),    -   (2) a carbamoyl group substituted by 1 or 2 C₁₋₆ alkyl groups        (e.g., methyl), or    -   (3) a carboxy group.

Compound I-7

Compound (I) wherein

-   X¹ is CH or N;-   X² is CR¹⁰ or N;-   R¹⁰ is a hydrogen atom or a halogen atom (e.g., fluorine atom);-   R¹ is a halogen atom (e.g., fluorine atom, chlorine atom) or a C₁₋₆    alkyl group (e.g., methyl);-   R² is a C₁₋₆ alkyl group (e.g., methyl) or a C₁₋₆ alkoxy group    (e.g., methoxy);-   R³ and R⁴ are each a hydrogen atom;-   R⁵ is a hydrogen atom;-   R⁶ is a hydrogen atom or a halogen atom (e.g., fluorine atom); and-   R⁷ is a carbamoyl group substituted by 1 or 2 (preferably 1)    substituents selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl, isopropyl,        isobutyl, tert-butyl) optionally substituted by 1 to 3        substituents selected from        -   (i) a halogen atom (e.g., fluorine atom),        -   (ii) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl) optionally            substituted by 1 to 3 (preferably 1) hydroxy groups,        -   (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,            dimethylcarbamoyl),        -   (iv) a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy),        -   (v) a hydroxy group,        -   (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic            group (e.g., oxetanyl, tetrahydrofuranyl, pyrrolidinyl,            tetrahydropyranyl, morpholinyl) optionally substituted by            one oxo group, and        -   (vii) a C₁₋₆ alkylsulfonyl group (e.g., methylsulfonyl),    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl, cyclobutyl,        bicyclo[1.1.1]pentyl) optionally substituted by 1 to 3        (preferably 1 or 2) substituents selected from a halogen atom        (e.g., fluorine atom), an optionally halogenated C₁₋₆ alkyl        group (e.g., methyl, difluoromethyl) and a cyano group, and    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., oxetanyl, thietanyl, tetrahydrofuranyl,        tetrahydropyranyl) optionally substituted by 1 to 3 (preferably        1 or 2) substituents selected from a C₁₋₆ alkyl group (e.g.,        methyl), an oxo group and a hydroxy group.

Compound I-8

Compound (I) wherein

-   X¹ is CH or N;

-   X² is CR¹⁰ or N;

-   R¹⁰ is a hydrogen atom or a halogen atom (e.g., fluorine atom);

-   R¹ is a halogen atom (e.g., fluorine atom, chlorine atom) or a C₁₋₆    alkyl group (e.g., methyl);

-   R² is a C₁₋₆ alkyl group (e.g., methyl) or a C₁₋₆ alkoxy group    (e.g., methoxy);

-   R³, R⁴, R⁵ and R⁶ are each a hydrogen atom; and

-   R⁷ is a 5- or 6-membered monocyclic aromatic heterocyclic group    selected from

-   

-   

-   

-   

-   

-   which is substituted by 1 to 3 (preferably 1 or 2) substituents    selected from    -   (a) a C₁₋₆ alkyl group (e.g., methyl, ethyl, tert-butyl)        optionally substituted by 1 to 3 substituents selected from a        halogen atom (e.g., fluorine atom), a C₃₋₁₀ cycloalkyl group        (e.g., cyclopropyl), a C₁₋₆ alkoxy group (e.g., methoxy), and a        mono- or di-C₁₋₆ alkyl-carbamoyl group (e.g.,        dimethylcarbamoyl),    -   (b) a C₃₋₁₀ cycloalkyl group (e.g., cyclopropyl), and    -   (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic        group (e.g., tetrahydropyranyl).

Preferable specific examples of the compound represented by the formula(I) include the compounds of Examples 1 - 94.

When compound (I) is in the form of a salt, examples of such saltinclude salts with inorganic base, an ammonium salt, salts with organicbase, salts with inorganic acid, salts with organic acid, salts withbasic or acidic amino acid, and the like.

Preferable examples of the salt with inorganic base include alkali metalsalts such as sodium salt, potassium salt and the like; alkaline earthmetal salts such as calcium salt, magnesium salt, barium salt and thelike; an aluminum salt, and the like.

Preferable examples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like.

Preferable examples of the salt with inorganic acid include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferable examples of the salt with organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidand the like.

Preferable examples of the salt with basic amino acid include salts witharginine, lysine, ornithine and the like.

Preferable examples of the salt with acidic amino acid include saltswith aspartic acid, glutamic acid and the like.

Among these salts, a pharmaceutically acceptable salt is preferable.When a compound has a basic functional group, examples of a preferablepharmaceutically acceptable salt include salts with inorganic acid suchas hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like, and salts with organic acid such as aceticacid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, methanesulfonic acid,p-toluenesulfonic acid and the like. In addition, when a compound has anacidic functional group, examples thereof include inorganic salts suchas alkali metal salts (e.g., sodium salt, potassium salt etc.), alkalineearth metal salts (e.g., calcium salt, magnesium salt, barium salt etc.)and the like, ammonium salt and the like.

Compound (I) may be a crystal, and both a single crystal and crystalmixtures are encompassed in the compound (I).

Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalsalt. Here, the cocrystal or cocrystal salt means a crystallinesubstance consisting of two or more particular substances which aresolids at room temperature, each having different physical properties(e.g., structure, melting point, heat of melting, hygroscopicity,solubility, stability etc.). The cocrystal and cocrystal salt can beproduced by cocrystallization method known per se.

Compound (I) encompasses solvates (e.g., hydrate) and non-solvateswithin the scope thereof. compound (I) may be a compound labeled orsubstituted with an isotope (e.g., ²H, ³H, ¹¹C, ¹⁴C, ¹⁸F, ³⁵S, ¹²⁵I) . Acompound labeled with or substituted by an isotope can be used, forexample, as a tracer used for Positron Emission Tomography (PET) (PETtracer), and is useful in the field of medical diagnosis and the like.

When compound (I) of the present invention has an asymmetric center,isomers such as enantiomer, diastereomer and the like may be present.Such isomers and a mixture thereof are all encompassed within the scopeof the present invention. When an isomer is formed due to theconformation or tautomerism, such isomers and a mixture thereof are alsoencompassed in compound (I) of the present invention.

The production method of the compound of the present invention isexplained in the following.

The starting materials and reagents used in each step in the followingproduction method, and the obtained compounds each may form a salt.Examples of the salt include those similar to the aforementioned saltsof the compound of the present invention and the like.

When the compound obtained in each step is a free compound, it can beconverted to a desired salt by a method known per se. Conversely, whenthe compound obtained in each step is a salt, it can be converted to afree form or a desired other kind of salt by a method known per se.

The compound obtained in each step can also be used for the nextreaction as a reaction mixture thereof or after obtaining a crudeproduct thereof. Alternatively, the compound obtained in each step canbe isolated and/or purified from the reaction mixture by a separationmeans such as concentration, crystallization, recrystallization,distillation, solvent extraction, fractionation, chromatography and thelike according to a conventional method.

When the starting materials and reagent compounds of each step arecommercially available, the commercially available products can be usedas they are.

In the reaction of each step, while the reaction time varies dependingon the reagents and solvents to be used, unless otherwise specified, itis generally 1 min – 48 hr, preferably 10 min – 8 hr.

In the reaction of each step, while the reaction temperature variesdepending on the reagents and solvents to be used, unless otherwisespecified, it is generally -78° C. to 300° C., preferably -78° C. to150° C.

In the reaction of each step, while the pressure varies depending on thereagents and solvents to be used, unless otherwise specified, it isgenerally 1 atm – 20 atm, preferably 1 atm – 3 atm.

In the reaction of each step, for example, microwave synthesizers suchas Initiator manufactured by Biotage and the like are sometimes used.While the reaction temperature varies depending on the reagents andsolvents to be used, unless otherwise specified, it is generally roomtemperature – 300° C., preferably 50° C. - 250° C. While the reactiontime varies depending on the reagents and solvents to be used, unlessotherwise specified, it is generally 1 min – 48 hr, preferably 1 min – 8hr.

In the reaction of each step, unless otherwise specified, a reagent isused in 0.5 equivalent - 20 equivalents, preferably 0.8 equivalent - 5equivalents, relative to the substrate. When a reagent is used as acatalyst, the reagent is used in 0.001 equivalent - 1 equivalent,preferably 0.01 equivalent - 0.2 equivalent, relative to the substrate.When the reagent is also a reaction solvent, the reagent is used in asolvent amount.

In the reaction of each step, unless otherwise specified, it isperformed without solvent or by dissolving or suspending in a suitablesolvent. Specific examples of the solvent include those described inExamples and the following.

-   alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol    and the like;-   ethers: diethyl ether, diphenyl ether, tetrahydrofuran,    1,2-dimethoxyethane and the like;-   aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;-   saturated hydrocarbons: cyclohexane, hexane and the like; amides:    N,N-dimethylformamide, N-methylpyrrolidone and the like;-   halogenated hydrocarbons: dichloromethane, carbon tetrachloride and    the like;-   nitriles: acetonitrile and the like;-   sulfoxides: dimethyl sulfoxide and the like;-   aromatic organic bases: pyridine and the like;-   acid anhydrides: acetic anhydride and the like;-   organic acids: formic acid, acetic acid, trifluoroacetic acid and    the like;-   inorganic acids: hydrochloric acid, sulfuric acid and the like;    esters: ethyl acetate and the like;-   ketones: acetone, methyl ethyl ketone and the like; and water.

Two or more kinds of the above-mentioned solvents may be used by mixingat an appropriate ratio.

When a base is used in the reaction of each step, for example, basesshown below or those described in Examples are used.

-   inorganic bases: sodium hydroxide, magnesium hydroxide and the like;-   organic bases: sodium carbonate, calcium carbonate, sodium hydrogen    carbonate and the like;-   organic bases: triethylamine, diethylamine, pyridine,    4-dimethylaminopyridine, N,N-dimethylaniline,    1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene,    imidazole, piperidine and the like;-   metal alkoxides: sodium ethoxide, potassium tert-butoxide and the    like;-   alkali metal hydrides: sodium hydride and the like;-   metal amides: sodium amide, lithium diisopropyl amide, lithium    hexamethyl disilazide and the like; and-   organic lithiums: n-butyllithium and the like.

Unless otherwise specified, the reaction of each step is performedaccording to a method known per se, for example, the methods describedin Jikken Kagaku Kouza 5th edition, vol. 13 -vol. 19 (The ChemicalSociety of Japan ed.); Shinjikken Kagaku Kouza (Courses in ExperimentalChemistry), vol. 14 - vol. 15 (The Chemical Society of Japan ed.); FineOrganic Chemistry rev. 2nd edition (L.F. Tietze, Th. Eicher, NANKODO);rev. Organic Name Reactions, Their Mechanism and Essence (Hideo Togo,Kodansha); ORGANIC SYNTHESES Collective Volume I - VII (John Wiley &Sons Inc); Modern Organic Synthesis in the Laboratory, A Collection ofStandard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY);Comprehensive Heterocyclic Chemistry III, Vol. 1 - Vol. 14 (ElsevierJapan KK); Strategic Applications of Named Reactions in OrganicSynthesis (translation supervisor Kiyoshi Tomioka, KAGAKUDOJIN);Comprehensive Organic Transformations (VCH Publishers Inc.), 1989 andthe like, or the methods described in the Examples.

In each step, protection or deprotection reaction of a functional groupis performed by the method known per se, for example, the methodsdescribed in “Protective Groups in Organic Synthesis, 4th Ed.” (TheodoraW. Greene, Peter G.M. Wuts) Wiley-Interscience, 2007; “Protecting Groups3rd Ed.” (P.J. Kocienski) Thieme, 2004 and the like, or the methodsdescribed in the Examples.

Examples of the protecting group of the hydroxyl group of alcohol andthe like and a phenolic hydroxyl group include ether protecting groupssuch as methoxymethyl ether, benzyl ether, tert-butyldimethylsilylether, tetrahydropyranyl ether and the like; carboxylate esterprotecting groups such as acetate ester and the like; sulfonate esterprotecting groups such as methanesulfonate ester and the like; carbonateester protecting groups such as tert-butylcarbonate and the like, andthe like.

Examples of the protecting group of the carbonyl group of aldehydeinclude acetal protecting groups such as dimethyl acetal and the like;cyclic acetal protecting groups such as 1,3-dioxane and the like, andthe like.

Examples of the protecting group of the carbonyl group of ketone includeketal protecting groups such as dimethyl ketal and the like; cyclicketal protecting groups such as 1,3-dioxane and the like; oximeprotecting groups such as O-methyloxime and the like; hydrazoneprotecting groups such as N,N-dimethylhydrazone and the like, and thelike.

Examples of the carboxyl protecting group include ester protectinggroups such as methyl ester and the like; amide protecting groups suchas N,N-dimethylamide and the like, and the like.

Examples of the thiol protecting group include ether protecting groupssuch as benzyl thioether and the like; ester protecting groups such asthioacetate ester, thiocarbonate, thiocarbamate and the like, and thelike.

Examples of the protecting group of an amino group and an aromaticheterocycle such as imidazole, pyrrole, indole and the like includecarbamate protecting groups such as benzyl carbamate and the like; amideprotecting groups such as acetamide and the like; alkylamine protectinggroups such as N-triphenylmethylamine and the like, sulfonamideprotecting groups such as methanesulfonamide and the like, and the like.

The protecting group can be removed by a method known per se, forexample, a method using acid, base, ultraviolet light, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyliodide, trimethylsilyl bromide), a reduction method and the like.

When a reduction reaction is performed in each step, examples of thereducing agent to be used include metal hydrides such as lithiumaluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride,diisobutylaluminum hydride (DIBAL-H), sodium borohydride,tetramethylammonium triacetoxyborohydride and the like; boranes such asborane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt;hydrogen; formic acid; triethylsilane and the like. When a carbon-carbondouble bond or triple bond is reduced, a method using a catalyst such aspalladium-carbon, Lindlar catalyst and the like is used.

When an oxidation reaction is performed in each step, examples of anoxidant to be used include peracids such as m-chloroperbenzoic acid(mCPBA), hydrogen peroxide, tert-butyl hydroperoxide and the like;perchlorates such as tetrabutylammonium perchlorate and the like;chlorates such as sodium chlorate and the like; chlorites such as sodiumchlorite and the like; periodic acids such as sodium periodate and thelike; high valent iodine reagents such as iodosylbenzene and the like;reagents containing manganese such as manganese dioxide, potassiumpermanganate and the like; leads such as lead tetraacetate and the like;reagents containing chrome such as pyridinium chlorochromate (PCC),pyridinium dichromate (PDC), Jones reagent and the like; halogencompounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone;sulfur trioxide pyridine complex; osmium tetraoxide; selenium dioxide;2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When a radical cyclization reaction is performed in each step, examplesof the radical initiator to be used include azo compounds such asazobisisobutyronitrile (AIBN) and the like; water-soluble radicalinitiators such as 4,4′-azobis-4-cyanopentanoic acid (ACPA) and thelike; triethylboron in the presence of air or oxygen; benzoyl peroxideand the like. In addition, examples of the radical reaction agent to beused include tributylstannane, tristrimethylsilylsilane,1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and thelike.

When the Wittig reaction is performed in each step, examples of theWittig reagent to be used include alkylidenephosphoranes and the like.Alkylidenephosphoranes can be prepared by a method known per se, forexample, by reacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is performed in each step, examples ofthe reagent to be used include phosphonoacetic acid esters such asmethyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and thelike; and bases such as alkali metal hydrides, organic lithiums and thelike.

When the Friedel-Crafts reaction is performed in each step, examples ofthe reagent to be used include a combination of Lewis acid and acidchloride, a combination of Lewis acid and alkylating agents (e.g., alkylhalides, alcohol, olefins and the like). Alternatively, an organic acidand an inorganic acid can also be used instead of the Lewis acid, andacid anhydride such as acetic anhydride and the like can also be usedinstead of acid chloride.

When an aromatic nucleophilic substitution reaction is performed in eachstep, a nucleophilic agent (e.g., amines, imidazole and the like) and abase (e.g., organic bases and the like) are used as the reagent.

When a nucleophilic addition reaction with carbanion, a nucleophilic1,4-addition reaction with carbanion (Michael addition reaction) or anucleophilic substitution reaction with carbanion is performed in eachstep, examples of the base to be used for developing carbanion includeorganic lithiums, metal alkoxides, inorganic bases, organic bases andthe like.

When the Grignard reaction is performed in each step, examples of theGrignard reagent include aryl magnesium halides such as phenyl magnesiumbromide and the like; and alkyl magnesium halides such as methylmagnesium bromide and the like. The Grignard reagent can be prepared bya method known per se, for example, by reacting alkyl halide or arylhalide with metal magnesium in ether or tetrahydrofuran as a solvent.

When the Knoevenagel condensation reaction is performed in each step, anactive methylene compound held between two electron-withdrawing groups(e.g., malonic acid, diethyl malonate, malononitrile and the like) and abase (e.g., organic bases, metal alkoxides, inorganic bases) are used asthe reagents.

When the Vilsmeier-Haack reaction is performed in each step, phosphorylchloride and an amide derivative (e.g., N,N-dimethylformamide and thelike) are used as the reagents.

When an azidation reaction of alcohols, alkyl halides or sulfonateesters is performed in each step, examples of the azidation agent to beused include diphenylphosphoryl azide (DPPA), trimethylsilyl azide,sodium azide and the like. For example, when alcohols are azidated, amethod using diphenylphosphoryl azide and1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), a method using trimethylsilylazide and the Lewis acid and the like can be employed.

When a reductive amination reaction is performed in each step, examplesof the reducing agent to be used include sodium triacetoxyborohydride,sodium cyanoborohydride, hydrogen, formic acid and the like. When thesubstrate is an amine compound, examples of the carbonyl compound to beused besides para-formaldehyde include aldehydes such as acetaldehydeand the like, ketones such as cyclohexanone and the like. When thesubstrate is a carbonyl compound, examples of the amines to be usedinclude ammonia, primary amines such as methylamine and the like;secondary amines such as dimethylamine and the like, and the like.

When the Mitsunobu reaction is performed in each step, azodicarboxylateesters (e.g., diethyl azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) and the like) and triphenylphosphine are used asthe reagents.

When an esterification reaction, amidation reaction or ureation reactionis performed in each step, examples of the reagent to be used includehalogenated acyl forms such as acid chloride, acid bromide and the like;and activated carboxylic acids such as acid anhydride, active esterform, sulfuric acid ester form and the like. Examples of the carboxylicacid activator include carbodiimide condensing agents such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) andthe like; triazine condensing agents such as4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholiniumchloride-n-hydrate (DMT-MM) and the like; carbonate ester condensingagents such as 1,1-carbonyldiimidazole (CDI) and the like;diphenylphosphoryl azide (DPPA);benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent);2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent); thionylchloride; lower alkyl haloformates such as ethyl chloroformate and thelike; O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); sulfuric acid; a combination thereof and thelike. When a carbodiimide condensing agent is used, additives such as1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP) and the like can be further added to thereaction.

When a coupling reaction is performed in each step, examples of themetal catalyst to be used include palladium compounds such aspalladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II),dichlorobis(triethylphosphine)palladium(II),tris(dibenzylideneacetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride and thelike; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) andthe like; rhodium compounds such as tris(triphenylphosphine)rhodium(III)chloride and the like; a cobalt compound; copper compounds such ascopper oxide, copper(I) iodide and the like; a platinum compound and thelike. A base may be further added to the reaction and examples of suchbase include inorganic bases and the like.

When a thiocarbonylation reaction is performed in each step,diphosphorus pentasulfide is representatively used as athiocarbonylating agent. Besides diphosphorus pentasulfide, a reagenthaving a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide(Lawesson reagent) and the like may also be used.

When the Wohl-Ziegler reaction is performed in each step, examples ofthe halogenating agent to be used include N-iodosuccinimide,N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfurylchloride and the like. Furthermore, the reaction can be accelerated byadding heat, light, radical initiators such as benzoyl peroxide,azobisisobutyronitrile and the like to the reaction.

When a halogenating reaction of a hydroxy group is performed in eachstep, examples of the halogenating agent to be used include acid halideof hydrohalic acid and inorganic acid; specifically, hydrochloric acid,thionyl chloride, phosphorus oxychloride and the like for chlorination,and 48% hydrobromic acid and the like for bromination. In addition, amethod of obtaining an alkyl halide form from alcohol by reacting withtriphenylphosphine and carbon tetrachloride or carbon tetrabromide, andthe like may be used. Alternatively, a method of synthesizing an alkylhalide form via a two-step reaction including conversion of alcohol tosulfonic acid ester, and reacting same with lithium bromide, lithiumchloride or sodium iodide may also be used.

When the Arbuzov reaction is performed in each step, examples of thereagent to be used include alkyl halides such as ethyl bromoacetate andthe like; and phosphites such as triethyl phosphite, tri(isopropyl)phosphite and the like.

When a sulfonic acid esterification reaction is performed in each step,examples of the sulfonylating agent to be used include methanesulfonylchloride, p-toluenesulfonyl chloride, methanesulfonic anhydride,p-toluenesulfonic anhydride and the like.

When hydrolysis reaction is performed in each step, an acid or a base isused as the reagent. In addition, when acid hydrolysis reaction oftert-butyl ester is performed, formic acid, triethylsilane and the likeare sometimes added to reductively trap the by-produced tert-butylcation.

When a dehydration reaction is performed in each step, examples of thedehydrating agent to be used include sulfuric acid, phosphoruspentaoxide, phosphorus oxychloride, N,N′-dicyclohexylcarbodiimide,alumina, polyphosphoric acid and the like.

Compound (I) can be produced by the method shown in the followingschemes or a method analogous thereto or the method described inExamples.

Compound (I) wherein X¹ is CH, i.e., compound (IA), can be produced fromcompound (1) by the following method.

In the reaction formulas, R¹¹ and R¹² are each a halogen atom, P is analcohol-protecting group and R¹, R², R⁵ to R⁷ and X² mean the same asabove.

Compound (2) can be produced by halogenation of compound (1) and ahalogenating agent such as bromine and the like.

Compound (3) can be produced by an amidation reaction of compound (2)and amines.

Compound (4) can be produced by a pyrimidinone ring formation reactionof compound (3) and N,N-dimethylformamide dimethyl acetal.

Compound (5) can be produced by a coupling reaction of compound (4) andbis(pinacolato)diboron in the presence of a metal catalyst.

Compound (7) can be produced by protecting alcohol of compound (4).

Compound (8) can be produced by a coupling reaction of compound (7) andbis(pinacolato)diboron in the presence of a metal catalyst.

Compound (9) can be produced by a coupling reaction of compound (8) andcompound (6) in the presence of a metal catalyst.

Compound (IA) can be produced by a coupling reaction of compound (5) andcompound (6) in the presence of a metal catalyst, or deprotection of thealcohol-protecting group of compound (9).

Compound (I) wherein X¹ is N, i.e., compound (II), can be produced fromcompound (3) by the following method.

In the reaction formulas, R¹, R², R⁵ to R⁷, R¹¹, R¹² and X² mean thesame as above.

Compound (10) can be produced by a triazinone ring formation reaction ofcompound (3) and sodium nitrite.

Compound (11) can be produced by a coupling reaction of compound (10)and bis(pinacolato)diboron in the presence of a metal catalyst.

Compound (II) can be produced by a coupling reaction of compound (11)and compound (6) in the presence of a metal catalyst.

Of compounds (IA) and (II), compound (13) wherein R⁷ is a carboxy groupand compound (14) wherein R⁷ is an optionally substituted carbamoylgroup can be produced from compound (5) or compound (11) by thefollowing method.

In the reaction formulas, R¹³ is a C₁₋₆ alkyl group, R^(7a) is anoptionally substituted carbamoyl group, and R¹, R², R⁵, R⁶, R¹², X¹ andX² mean the same as above.

Compound (12) can be produced by a coupling reaction of compound (5) orcompound (11) and compound (6A) in the presence of a metal catalyst.

Compound (13) can be produced by hydrolysis of compound (12) .

Compound (14) can be produced by an amidation reaction of compound (13)and amines.

Of compounds (IA) and (II), compound (18) wherein R⁷ is an optionallysubstituted pyrazolyl group can also be produced from compound (5) orcompound (11) by the following method.

In the reaction formulas, R¹⁴ and R¹⁶ are each a halogen atom, R¹⁵ is anoptionally substituted hydrocarbon group or optionally substitutedheterocyclic group and R¹, R², R⁵, R⁶, R¹², X¹ and X² mean the same asabove.

Compound (15) can be produced by a coupling reaction of compound (5) orcompound (11) and compound (6B) in the presence of a metal catalyst.

Compound (18) can be produced by a coupling reaction of compound (15)and compound (16) in the presence of a metal catalyst.

Compound (19) can be produced by a coupling reaction of compound (15)and compound (17) in the presence of a metal catalyst.

Compound (18) can be produced by an alkylation reaction of compound (19)and R¹⁵-R¹⁶ in the presence of a base.

Of compounds (I), compound (23) wherein one of R³ and R⁴ is a halogenatom and the other is a hydrogen atom, and compound (25) wherein one ofR³ and R⁴ is an optionally substituted C₁₋₆ alkoxy group and the otheris a hydrogen atom can be produced from compound (20) by the followingmethod.

In the reaction formulas, R¹⁷ and R¹⁸ are each a halogen atom, R¹⁹ is anoptionally substituted C₁₋₆ alkyl group, and P, R¹, R², R⁵, R⁶, R⁷, R¹¹,X¹ and X² mean the same as above.

Compound (22) can be produced by a Grignard reaction of compound (20)and compound (21).

Compound (23) can be produced by halogenating the hydroxy group ofcompound (22) and deprotection of the alcohol-protecting group. As ahalogenating agent, a fluorinating agent such as (diethylamino)sulfurtrifluoride and the like, and the like can be mentioned besides theaforementioned reagents.

Compound (25) can be produced by alkylating the hydroxy group ofcompound (22) with alkyl halide (24) and deprotection of thealcohol-protecting group.

Of compounds (I), compound (28) wherein one of R³ and R⁴ is anoptionally substituted C₁₋₆ alkyl group and the other is a hydrogen atomcan be produced from compound (20) by the following method.

In the reaction formulas, R²⁰ is an optionally substituted C₁₋₆ alkylgroup, and P, R¹, R², R⁵, R⁶, R⁷, R¹¹, X¹ and X² mean the same as above.

Compound (27) can be produced by a Grignard reaction of compound (20)and compound (26).

Compound (28) can be produced by reducing the hydroxy group of compound(27) and deprotection of the alcohol-protecting group.

Compound (29) can be produced by a coupling reaction of compound (20)and bis(pinacolato)diboron in the presence of a metal catalyst.

Compound (30) can be produced by a coupling reaction of compound (29)and compound (26) in the presence of p-toluenesulfonyl hydrazide and aninorganic base according to the method described in (document)Tetrahedron, 73, 785-793 (2017). As the inorganic base, potassiumcarbonate, potassium phosphate and the like can be mentioned.

Compound (28) can be produced by deprotection of the alcohol-protectinggroup of compound (30).

Compound (1), compound (2), amines, compound (6), compound (6A),compound (6B), compound (16), compound (17), compound (20), compound(21), compound (26), R¹⁵-R^(16,) R¹⁸-R¹⁹, N,N-dimethylformamide dimethylacetal and sodium nitrite used as starting materials for the productionof Compounds (IA) and (II) may be commercially available products or canbe produced by a method known per se.

When compounds (IA) and (II) have an optical isomer, a stereoisomer, aregioisomer or a rotamer, these are also encompassed in compound (I),and can be obtained as a single product according to synthesis andseparation methods known per se. For example, when compounds (IA) and(II) contain an optical isomer, an optical isomer resolved from thesecompounds is also encompassed in compounds (IA) and (II).

The optical isomer can be produced according to a method known per se.To be specific, an optically active synthetic intermediate is used, orthe final racemate product is subjected to optical resolution accordingto a conventional method to give an optical isomer.

For example, the method of optical resolution may be a method known perse, such as a fractional recrystallization method, a chiral columnmethod, a diastereomer method etc.

1) Fractional Recrystallization Method

A method wherein a salt with a racemate with an optically activecompound (e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid,(-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine,cinchonine, (-)-cinchonidine, brucine etc.) is formed, which isseparated by a fractional recrystallization method, and if desired, aneutralization step to give a free optical isomer.

2) Chiral Column Method

A method wherein a racemate or a salt thereof is applied to a column forseparation of an optical isomer (a chiral column) to allow separation.In the case of a liquid chromatography, for example, a mixture of theoptical isomers is applied to a chiral column such as ENANTIO-OVM(manufactured by Tosoh Corporation), CHIRAL series manufactured byDaicel Corporation and the like, and developed with water, variousbuffers (e.g., phosphate buffer, etc.) and organic solvents (e.g.,ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid,diethylamine etc.), solely or as a mixed solution thereof to separatethe optical isomer.

3) Diastereomer Method

A method wherein a racemic mixture is prepared into a diastereomericmixture by chemical reaction with an optically active reagent, which ismade into a single substance by a typical separation means (e.g., afractional recrystallization method, a chromatography method etc.) andthe like, and is subjected to a chemical treatment such as hydrolysisreaction and the like to remove an optically active reagent moiety,whereby an optical isomer is obtained. For example, when compound (I)contains hydroxy group, or primary or secondary amino group within amolecule, the compound and an optically active organic acid (e.g., MTPA[α-methoxy-α-(trifluoromethyl)phenylacetic acid], (-)-menthoxyaceticacid etc.) and the like are subjected to condensation reaction to givediastereomers of the ester compound or the amide compound, respectively.When compound (I) has a carboxylic acid group, this compound and anoptically active amine or an optically active alcohol reagent aresubjected to condensation reaction to give diastereomers of the amidecompound or the ester compound, respectively. The separated diastereomeris converted to an optical isomer of the original compound by acidhydrolysis or base hydrolysis reaction.

When compound (I) is obtained as a free compound, the compound can beconverted to an objective salt according to a method known per se or amethod analogous thereto. Conversely, when it is obtained as a salt, thesalt can be converted to a free form or other objective salt by a methodknown per se or a method analogous thereto.

Compound (I) may be a prodrug, and the prodrug of compound (I) refers toa compound which is converted to compound (I) as a result of a reactionwith an enzyme, gastric acid, etc. under physiological conditions invivo, thus a compound that undergoes enzymatic oxidation, reduction,hydrolysis etc. to convert to compound (I) and a compound that undergoeshydrolysis and the like by gastric acid, etc. to convert to compound(I).

Examples of the prodrug for compound (I) include a compound obtained bysubjecting an amino group in compound (I) to acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation,t-butylation and the like); a compound obtained by subjecting a hydroxygroup in compound (I) to acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting a hydroxy group incompound (I) to acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation ordimethylaminomethylcarbonylation and the like); a compound obtained bysubjecting a carboxyl group in compound (I) to esterification oramidation (e.g., a compound obtained by subjecting a carboxyl group incompound (I) to ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification ormethylamidation and the like) and the like. Any of these compounds canbe produced from compound (I) according to a method known per se.

A prodrug of compound (I) may also be one which is converted to compound(I) under physiological conditions as described in “IYAKUHIN no KAIHATSU(Development of Pharmaceuticals)”, Vol. 7, Design of Molecules, p.163-198 (HIROKAWA SHOTEN).

Compound (I) may be used for the prophylaxis or treatment of diseases,for example, constipation, for example, neurogenic constipation(constipation associated with diseases such as Parkinson’s disease,multiple sclerosis, spinal cord injury, Alzheimer’s disease,Hirschsprung’s syndrome, Chagas’ disease, and the like), idiopathicconstipation, functional constipation, flaccid constipation, irritablebowel syndrome with constipation, constipation possibly complicated byother disease (Parkinson’s disease, spinal cord injury, multiplesclerosis, etc.), age-related constipation, various drug-inducedconstipation (opioid agonist-induced constipation and the like), primarychronic constipation, drug-induced constipation (opioid, anticholinergicagent, calcium antagonist, anticancer agent, heavy metal toxicosis, andthe like), constipation associated with underlying diseases such asendocrine diseases or metabolic abnormality (hypopituitarism,hypothyroidism, pheochromocytoma, and the like), muscle abnormalitiesdisease (familial visceral skeletal muscle atrophy, scleroderma,amyloidosis, progressive systemic sclerosis, and the like), metabolicdiseases (diabetes, porphyria, uremia, hypokalemia, hypercalcemia, andthe like) and the like, and gastric hypomotility such as gastroparalysisand the like, post-operative gastrointestinal paralysis, uppergastrointestinal motility disorder and discomfort, nausea, vomiting,erosive esophagitis, gastric ulcer, duodenal ulcer, antiinflammatoryagents (non-steroidal antiinflammatory agents)-induced gastrointestinaldisorder, dysuria, bladder functional disorder and the like in mammals(e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey,human etc.).

Since compound (I) may have a cholinergic muscarinic M1 receptorpositive allosteric modulator activity, it is expected to provide anexcellent prophylactic or therapeutic effect for the above-mentioneddiseases.

Generally, it is desirable that the therapeutic drugs for constipationexhibit effect promptly after administration and then the effectdisappears quickly. Compound (I) is expected to show superiorpharmacokinetics as a therapeutic drug for constipation and may beexpected to exhibit effect within, for example, 3 hr afteradministration, preferably 2 hr after administration, further preferably1 hr after administration, and the effect may be expected to disappearquickly thereafter.

Cholinergic muscarinic M1 receptor is known to express in the brain andgastrointestinal nerve plexus. Compound (I) is expected to show lowcentral nervous system permeability, function efficiently in peripheryand show excellent effect as a therapeutic drug for constipation.Regarding central nervous system permeability, for example, correctedefflux ratio of MDR1 in MDR1 membrane permeability test is preferablynot less than 2.0, more preferably not less than 3.0, and furthermorepreferably not less than 5.0.

Since compound (I) may be expected to be excellent in solubility inwater, the Japanese Pharmacopoeia dissolution test 2nd fluid, or theJapanese Pharmacopoeia disintegration test 2nd fluid, excellent inpharmacokinetics (e.g., plasma drug half-life, metabolic stability, CYPinhibition), show low toxicity (e.g., more excellent as a medicament interms of acute toxicity, chronic toxicity, genetic toxicity,reproductive toxicity, cardiotoxicity, drug interaction,carcinogenicity, phototoxicity and the like), and may also haveexcellent properties as a pharmaceutical product such as a few sideeffects and the like, it can be safely administered orally orparenterally to a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog,bovine, sheep, monkey, human and the like). Examples of the “parenteral”include intravenous, intramuscular, subcutaneous, intra-organ,intranasal, intradermal, instillation, intracerebral, intrarectal,intravaginal, intraperitoneal and intratumor administrations,administration to the vicinity of tumor etc. and direct administrationto the lesion.

A medicament containing compound (I) (sometimes to be abbreviated as“medicament of the present invention” in the present specification) mayhave any form (preparation form) of a solid preparation such as powder,granule, tablet, capsule, orally disintegrable film and the like, or aliquid agent such as syrup, emulsion, injection and the like.

The medicament of the present invention may be produced by aconventional method such as blending, kneading, granulation, tableting,coating, sterilization treatment, emulsification and the like accordingto the form of the preparation. As for the production of thepreparation, for example, each item of the Japanese PharmacopoeiaPreparation General Rules and the like can be referred to. In addition,the medicament of the present invention may be formed into asustained-release preparation containing an active ingredient and abiodegradable polymer compound. The sustained-release preparation can beproduced according to the method described in JP-A-9-263545.

In the medicament of the present invention, the content of compound (I)varies depending on the form of the preparation, but is generally 0.01to 100% by weight, preferably 0.1 to 50% by weight, more preferably 0.5to 20% by weight, as the amount of compound (I) relative to the wholepreparation (whole medicament).

Compound (I) may be used alone or in admixture with a suitable,pharmacologically acceptable carrier, for example, excipients (e.g.,starch, lactose, white soft sugar, calcium carbonate, calcium phosphate,etc.), binders (e.g., starch, arabic gum, carboxymethyl cellulose,hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin,polyvinylpyrrolidone, etc.), lubricants (e.g., stearic acid, magnesiumstearate, calcium stearate, talc, etc.), disintegrants (e.g., calciumcarboxymethylcellulose, talc, etc.), diluents (e.g., water forinjection, physiological saline, etc.) and if desired, with theadditives (e.g., a stabilizer, a preservative, a colorant, a fragrance,a solubilizing agent, an emulsifier, a buffer, an isotonic agent, etc.)and the like, by a conventional method, which is processed into a dosageform of a solid agent such as powder, fine granule, granule, tablet,capsule and the like or a liquid form such as injection and the like,and administered orally or parenterally. When compound (I) is formed asa preparation for topical administration, it can also be directlyadministered to the affected part of an articular disease. In this case,an injection is preferable. compound (I) can also be administered as aparenteral agent for topical administration (e.g., intramuscularinjection, subcutaneous injection, organ injection, injection to thevicinity of a joint and the like, solid preparation such as implant,granule, powder and the like, liquid such as suspension and the like,ointment etc.) and the like.

For formulation into an injection, for example, compound (I) isformulated into an aqueous suspension with a dispersing agent (e.g.,surfactant such as Tween 80, HCO-60 and the like, polysaccharides suchas carboxymethylcellulose, sodium alginate, hyaluronic acid and thelike, polysorbate etc.), preservative (e.g., methylparaben,propylparaben etc.), isotonic agent (e.g., sodium chloride, mannitol,sorbitol, glucose etc.), buffer (e.g., calcium carbonate etc.), pHadjuster (e.g., sodium phosphate, potassium phosphate etc.) and the liketo give a practical preparation for injection. In addition, an oilysuspension can be obtained by dispersing the compound together withvegetable oil such as sesame oil, corn oil and the like or a mixturethereof with a phospholipid such as lecithin and the like, ormedium-chain fatty acid triglyceride (e.g., miglyol 812 etc.) to give aninjection to be actually used.

The dose of compound (I) varies depending on the subject ofadministration, administration route and symptoms and is notparticularly limited. For example, for oral administration to adultpatients (body weight adult 40 to 80 kg, for example, 60 kg) withconstipation, the dose may be, for example, 0.001 to 1000 mg/kg bodyweight/day, preferably 0.01 to 100 mg/kg body weight/day, morepreferably 0.1 to 10 mg/kg body weight/day, as compound (I). This amountmay be administered in one to three portions per day.

The medicament of the present invention may be able to use the compound(I) solely or as a pharmaceutical composition of compound (I) mixed witha pharmacologically acceptable carrier according to a method known perse (e.g., the method described in the Japanese Pharmacopoeia etc.) asthe production method of a pharmaceutical preparation. The medicament ofthe present invention may be administered safely in the form of, forexample, a pharmaceutical composition such as tablet (includingsugar-coated tablet, film-coated tablet, sublingual tablet, orallydisintegrating tablet, buccal and the like), pill, powder, granule,capsule (including soft capsule, microcapsule), troche, syrup, liquid,emulsion, suspension, release control preparation (e.g.,immediate-release preparation, sustained-release preparation,sustained-release microcapsule), aerosol, film (e.g., orallydisintegrating film, oral mucosa-adhesive film), injection (e.g.,subcutaneous injection, intravenous injection, intramuscular injection,intraperitoneal injection), drip infusion, transdermal absorption typepreparation, ointment, lotion, adhesive preparation, suppository (e.g.,rectal suppository, vaginal suppository), pellet, nasal preparation,pulmonary preparation (inhalant), eye drop and the like, orally orparenterally (e.g., intravenous, intramuscular, subcutaneous,intraorgan, intranasal, intradermal, instillation, intracerebral,intrarectal, intravaginal, intraperitoneal, lesion and the like).

As the aforementioned “pharmacologically acceptable carrier”, variousorganic or inorganic carriers conventionally used as preparationmaterials (starting materials) may be used. For example, excipient,lubricant, binder, disintegrant and the like may be used for solidpreparations, and solvent, solubilizing agent, suspending agent,isotonic agent, buffer, soothing agent and the like may be used forliquid preparations. Where necessary, preparation additives such aspreservative, antioxidant, colorant, sweetening agent and the like mayalso be used.

Examples of the excipient include lactose, white soft sugar, D-mannitol,starch, corn starch, crystalline cellulose, light anhydrous silicic acidand the like.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, white soft sugar,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, sodium carboxymethyl starch,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as poly(vinylalcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffer include buffer solutions such as phosphate salts,acetate salts, carbonate salts, citrate salts and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include p-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Examples of the antioxidant include sulfite salts, ascorbic acid,α-tocopherol and the like.

While the pharmaceutical composition varies according to the dosageform, administration method, carrier and the like, it may be producedaccording to a conventional method by adding compound (I) in aproportion of generally 0.01 - 100%(w/w), preferably 0.1 - 95%(w/w), ofthe total amount of the preparation.

Compound (I) may be used in combination with other active ingredients(hereinafter to be abbreviated as concomitant drug).

Examples of the concomitant drug include the following. Prokinetic agent(cholinesterase inhibitor (neostigmine, physostigmine etc.), 5-HT₄agonist, ghrelin agonist (capromorelin etc.), motilin receptor agonist(camicinal, erythromycin etc.), opioid antagonist (naltrexone, naloxegoletc.)), intestinal water secretion promoter (guanylate cyclase C agonist(linaclotide etc.), chloride channel 2 opener (lubiprostone etc.),sodium/proton exchanger 3 inhibitor (tenapanor etc.)), anti-constipationdrug (sennoside, magnesium oxide, magnesium hydroxide, bisacodyl,polycarbophil calcium, laxative sugars (lactulose etc.), laxoberon,crude drug having an anti-constipation action (psyllium etc.) etc.),benzodiazepine (chlordiazepoxide, diazepam, potassium clorazepate,lorazepam, clonazepam, alprazolam etc.), L-type calcium channelinhibitor (pregabalin etc.), tricyclic or tetracyclic antidepressant(imipramine hydrochloride, amitriptyline hydrochloride, desipraminehydrochloride, clomipramine hydrochloride etc.), selective serotoninreuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride,citalopram hydrobromide, sertraline hydrochloride, paroxetinehydrochloride, escitalopram oxalate etc.), serotonin-noradrenalinereuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride,desvenlafaxine hydrochloride etc.), noradrenaline reuptake inhibitor(reboxetine mesylate etc.), noradrenaline-dopamine reuptake inhibitor(bupropion hydrochloride etc.), mirtazapine, trazodone hydrochloride,nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate,5-HT_(1A) agonist (buspirone hydrochloride, tandospirone citrate,osemozotan hydrochloride etc.), 5-HT₃ antagonist (cyamemazine etc.),heart non-selective β inhibitor (propranolol hydrochloride, oxprenololhydrochloride etc.), histamine H₁ antagonist (hydroxyzine hydrochlorideetc.), therapeutic drug for schizophrenia (chlorpromazine, haloperidol,sulpiride, clozapine, trifluoperazine hydrochloride, fluphenazinehydrochloride, olanzapine, quetiapine fumarate, risperidone,aripiprazole etc.), CRF antagonist, other antianxiety drug (meprobamateetc.), tachykinin antagonist (aprepitant, saredutant etc.), medicamentthat acts on metabotropic glutamate receptor, CCK antagonist, β3adrenaline antagonist (amibegron hydrochloride etc.), GAT-1 inhibitor(tiagabine hydrochloride etc.), N-type calcium channel inhibitor,carbonic anhydrase II inhibitor, NMDA glycine moiety agonist, NMDAantagonist (memantine etc.), peripheral benzodiazepine receptor agonist,vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1aantagonist, phosphodiesterase inhibitor, opioid agonist, uridine,nicotinic acid receptor agonist, thyroid hormone (T3, T4), TSH, TRH, MAOinhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemideetc.), 5-HT_(2A) antagonist, 5-HT_(2A) inverse agonist, COMT inhibitor(entacapone etc.), therapeutic drug for bipolar disorder (lithiumcarbonate, sodium valproate, lamotrigine, riluzole, felbamate etc.),cannabinoid CB1 antagonist (rimonabant etc.), FAAH inhibitor, sodiumchannel inhibitor, anti-ADHD drug (methylphenidate hydrochloride,methamphetamine hydrochloride etc.), therapeutic drug for alcoholism,therapeutic drug for autisma, therapeutic drug for chronic fatiguesyndrome, therapeutic drug for convulsion, therapeutic drug forfibromyalgia syndrome, therapeutic drug for headache, therapeutic drugfor insomnia (etizolam, zopiclone, triazolam, zolpidem, ramelteon,indiplon etc.), therapeutic drug for quitting smoking, therapeutic drugfor myasthenia gravis, therapeutic drug for cerebral infarction,therapeutic drug for mania, therapeutic drug for hypersomnia,therapeutic drug for pain, therapeutic drug for dysthymia, therapeuticdrug for autonomic ataxia, therapeutic drug for male and female sexualdysfunction, therapeutic drug for migraine, therapeutic drug forpathological gambler, therapeutic drug for restless legs syndrome,therapeutic drug for substance addiction, therapeutic drug foralcohol-related syndrome, therapeutic drug for irritable bowel syndrome,therapeutic drug for Alzheimer’s disease (donepezil, galanthamine,memantine, rivastigmine etc.), therapeutic drug for Parkinson’s disease(levodopa, carbidopa, benserazide, selegiline, rasagiline, zonisamide,entacapone, amantadine, talipexole, pramipexole, ropinirole, rotigotine,apomorphine, cabergoline, pergolide, bromocriptine, istradefylline,trihexyphenidyl, biperiden, piroheptine, profenamine, promethazine,droxidopa, combination of those drugs etc.), therapeutic drug forParkinson’s disease dementia (rivastigmine), therapeutic drug for Lewybody dementia (donepezil), therapeutic drug for ALS (riluzole,neurotrophic factor etc.), therapeutic drug for lipid abnormality suchas cholesterol-lowering drug (statin series (pravastatin sodium,atorvastatin, simvastatin, rosuvastatin etc.), fibrate (clofibrateetc.), squalene synthetase inhibitor), therapeutic drug for behaviorabnormalities or suppressant of dromomania due to dementia (sedatives,antianxiety drug etc.), apoptosis inhibitor, antiobesity drug,therapeutic drug for diabetes, therapeutic drug for hypertension,therapeutic drug for hypotension, therapeutic drug for rheumatism(DMARD), anticancer agent, therapeutic drug for hypothyroidism (PTH),calcium receptor antagonist, sex hormone or a derivative thereof(progesterone, estradiol, estradiol benzoate etc.), neuronaldifferentiation promoter, nerve regeneration promoter, non-steroidalanti-inflammatory drug (meloxicam, tenoxicam, indomethacin, ibuprofen,celecoxib, rofecoxib, aspirin etc.), steroid (dexamethasone, cortisoneacetate etc.), anti-cytokine drug (TNF inhibitor, MAP kinase inhibitoretc.), antibody medicament, nucleic acid or nucleic acid derivative,aptamer drug and the like.

By combining compound (I) and a concomitant drug, a superior effect suchas

-   (1) the dose may be reduced as compared to single administration of    the compound (I) or a concomitant drug,-   (2) the drug to be combined with the compound (I) may be selected    according to the condition of patients (mild case, severe case and    the like),-   (3) the period of treatment may be set longer by selecting a    concomitant drug having different action and mechanism from the    compound (I),-   (4) a sustained treatment effect may be designed by selecting a    concomitant drug having different action and mechanism from the    compound (I),-   (5) a synergistic effect may be afforded by a combined use of the    compound (I) and a concomitant drug, and the like, can be achieved.

Hereinafter compound (I) and a concomitant drug used in combination arereferred to as the “combination agent of the present invention”.

When using the combination agent of the present invention, theadministration time of compound (I) and the concomitant drug is notrestricted, and compound (I) or a pharmaceutical composition thereof andthe concomitant drug or a pharmaceutical composition thereof can beadministered to an administration subject simultaneously, or may beadministered at different times. The dosage of the concomitant drug maybe determined according to the dose clinically used, and can beappropriately selected depending on an administration subject,administration route, disease, combination and the like.

The administration mode of the combination agent of the presentinvention is not particularly restricted, and it is sufficient thatcompound (I) and the concomitant drug are combined in administration.Examples of the administration mode include the following methods:

-   (1) administration of a single preparation obtained by    simultaneously processing compound (I) and the concomitant drug,-   (2) simultaneous administration of two kinds of preparations of    compound (I) and the concomitant drug, which have been separately    produced, by the same administration route, (3) administration of    two kinds of preparations of compound (I) and the concomitant drug,    which have been separately produced, by the same administration    route in a staggered manner, (4) simultaneous administration of two    kinds of preparations of compound (I) and the concomitant drug,    which have been separately produced, by different administration    routes, (5) administration of two kinds of preparations of    compound (I) and the concomitant drug, which have been separately    produced, by different administration routes in a staggered manner    (e.g., administration in the order of compound (I) and the    concomitant drug, or in the reverse order) and the like.

The combination agent of the present invention can be expected to showlow toxicity. For example, compound (I) or(and) the aforementionedconcomitant drug can be combined with a pharmacologically acceptablecarrier according to the known method to prepare a pharmaceuticalcomposition such as tablets (including sugar-coated tablet andfilm-coated tablet), powders, granules, capsules (including softcapsule), liquids, injections, suppositories, sustained-release agents,etc. These compositions may be administered safely orally or non-orally(e.g., topical, rectal, intravenous administration etc.). Injection maybe administered intravenously, intramuscularly, subcutaneously, or byintraorgan administration or directly to the lesion.

As the pharmacologically acceptable carriers that may be used for theproduction of a combination agent in the present invention, variousorganic or inorganic carrier substances conventionally used aspreparation materials may be used. For solid preparations, for example,excipient, lubricant, binder and disintegrant may be used. For liquidpreparations, for example, solvent, solubilizing agent, suspendingagent, isotonic agent, buffering agent, soothing agent and the like maybe used. Where necessary, a suitable amount of conventionalpreservative, antioxidant, colorant, sweetening agent, adsorbent,wetting agent and the like may be used as appropriate.

Examples of the excipient include lactose, white soft sugar, D-mannitol,starch, corn starch, crystalline cellulose, light anhydrous silicic acidand the like.

Examples of the lubricant include magnesium stearate, calcium stearate,talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, white soft sugar,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, sodium carboxymethyl starch,L-hydroxypropylcellulose and the like.

Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizing agent include polyethylene glycol,propylene glycol, D-mannitol, benzyl benzoate, ethanol,trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodiumcitrate and the like.

Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid,lecithin, benzalkonium chloride, benzetonium chloride, glycerinmonostearate and the like; hydrophilic polymers such as poly(vinylalcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like; and the like.

Examples of the isotonic agent include glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol and the like.

Examples of the buffer include buffer solutions such as phosphate salts,acetate salts, carbonate salts, citrate salts and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include p-oxybenzoate esters,chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid,sorbic acid and the like.

Examples of the antioxidant include sulfite salts, ascorbic acid,α-tocopherol and the like.

The mixing ratio of compound (I) to the concomitant drug in thecombination agent of the present invention can be appropriately selecteddepending on an administration subject, administration route, diseasesand the like.

For example, the content of compound (I) in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to 100 wt%, preferably from about 0.1 to 50 wt%,further preferably from about 0.5 to 20 wt%, based on the wholepreparation.

The content of the concomitant drug in the combination agent of thepresent invention differs depending on the form of a preparation, andusually from about 0.01 to 100 wt%, preferably from about 0.1 to 50 wt%,further preferably from about 0.5 to 20 wt%, based on the wholepreparation.

The content of additives such as a carrier and the like in thecombination agent of the present invention differs depending on the formof a preparation, and usually from about 1 to 99.99 wt%, preferably fromabout 10 to 90 wt%, based on the whole preparation.

When compound (I) and a concomitant drug are separately formulated intopreparations, the contents thereof are similar to the above.

EXAMPLES

The present invention is explained in detail in the following byreferring to Examples, Experimental Examples and Formulation Examples,which are not to be construed as limitative, and the invention may bechanged within the scope of the present invention.

In the following Examples, the “room temperature” generally means about10° C. to about 35° C. The ratios indicated for mixed solvents arevolume mixing ratios, unless otherwise specified. % means wt%, unlessotherwise specified.

Elution in column chromatography in the Examples was performed underobservation by TLC (Thin Layer Chromatography) unless particularlyindicated. In the TLC observation, 60 F₂₅₄ manufactured by Merck wasused as a TLC plate, and the solvent used as an eluent in the columnchromatography was used as an elution solvent. For detection, a UVdetector was employed. In silica gel column chromatography, theindication of NH means use of aminopropylsilane-bonded silica gel, andthe indication of Diol means use of3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparativeHPLC (high performance liquid chromatography), the indication of C18means use of octadecyl-bonded silica gel. The ratio of elution solventsis, unless otherwise specified, a volume mixing ratio.

For the analysis of ¹H NMR, ACD/SpecManager (trade name) software andthe like were used. Very mild peaks for protons of a hydroxy group, anamino group and the like may not be described.

MS was measured by LC/MS. As ionization method, ESI method or APCImethod was used. The data indicates those found. Generally, molecularion peaks are observed but may sometimes be observed as a fragment ion.In the case of a salt, generally, a molecular ion peak or a fragment ionpeak of a free form is observed.

The unit of the sample concentration (c) by optical rotation ([α]_(D))is g/100 mL.

Elemental analytical value (Anal.) shows calculated value (Calcd) andmeasured value (Found).

The peak in powder X-ray diffraction in the Examples means a peakmeasured using Cu Kα ray as a radiation source and Ultima IV (RigakuCorporation, Japan) at room temperature. The measurement conditions areas follows.

-   Electric pressure/Electric current: 40 kV/50 mA-   Scan speed: 6 degree/min-   Scan range of 2 Theta: 2-35 degree

The crystallinity by powder X-ray diffraction in the Examples wascalculated by the Hermans method.

In Examples, the following abbreviations are used.

-   mp: melting point-   MS: mass spectrum-   M: mol concentration-   N: normality-   CDCl₃: deuterochloroform-   DMSO-d₆: hexadeuterodimethyl sulfoxide-   CD₃OD: tetradeuteromethanol-   ¹H NMR: proton nuclear magnetic resonance-   LC/MS: liquid chromatography mass spectrometer-   ESI: electrospray ionization-   APCI: atmospheric pressure chemical ionization-   AIBN: azobisisobutyronitrile-   DIPEA: N,N-diisopropylethylamine-   DMA: N,N-dimethylacetamide-   DME: dimethoxyethane-   DMF: N,N-dimethylformamide-   DMSO: dimethyl sulfoxide-   EtOH: ethanol-   HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   IPE: diisopropyl ether-   MeOH: methanol-   MEK: methyl ethyl ketone-   NBS: N-bromosuccinimide-   NCS: N-chlorosuccinimide-   PdCl₂(Amphos)₂:    bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)-   PdCl₂(dppf): 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)    dichloride-   Pd(PPh₃)₂Cl₂: bis(triphenylphosphine)palladium(II) dichloride TEA:    triethylamine-   TFA: trifluoroacetic acid-   THF: tetrahydrofuran

Example 1 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitolA) 2-amino-5-bromo-3,4-dimethylbenzoic Acid

To a mixture of 2-amino-3,4-dimethylbenzoic acid (10 g) and DMSO (100mL) was added hydrobromic acid (48% v/v, 35 mL) at 0° C., and themixture was stirred at room temperature for 20 hr. To the reactionmixture was added water (150 mL) at 0° C. and the mixture was stirred.The precipitate was collected by filtration, washed with water and driedto give the title compound ( 13.23 g).

MS, found: 244.1, 246.0.

B)3-(amino-5-bromo-3,4-dimethylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol

To a mixture of 2-amino-5-bromo-3,4-dimethylbenzoic acid (10 g),3-amino-1,5-anhydro-2,3-dideoxy-L-threo-pentitol hydrochloride ( 6.29g), HATU ( 18.69 g) and DMF (100 mL) was added TEA ( 14.28 mL) at roomtemperature, and the mixture was stirred overnight. To the reactionmixture were added water and saturated aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate. The aqueouslayer was extracted with ethyl acetate/THF. The organic layer was washedwith water and saturated brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was crystallized fromethyl acetate/IPE and the precipitate was collected by filtration andwashed with IPE to give the title compound ( 14.19 g).

MS, found: 343.1, 345.1.

C)1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

A mixture of3-((2-amino-5-bromo-3,4-dimethylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol( 14.19 g) and N,N-dimethylformamide dimethyl acetal ( 71.8 mL) wasstirred at 90° C. under a nitrogen atmosphere for 3 hr. After cooling toroom temperature, tert-butyl methyl ether (50 mL) was added, and thereaction mixture was stirred. The precipitate was collected byfiltration and washed with tert-butyl methyl ether to give the titlecompound ( 11.0 g).

MS, found: 353.1, 355.1.

D)1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol

To a mixture of1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol( 5.00 g), bis(pinacolato)diboron ( 7.19 g), potassium acetate ( 6.95 g)and toluene (100 mL) was added Pd(PPh₃)₂Cl₂ ( 0.497 g), and the mixturewas stirred under an argon atmosphere at 100° C. overnight. Theinsoluble material was filtered off, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (Diol, ethyl acetate/hexane) to give the title compound (7.56 g). The compound was used in the next step without furtherpurification. MS: [M+H]⁺ 401.2.

E) 6-methyl-1H-pyrazol-3-yl)nicotinaldehyde

To a mixture of 6-chloronicotinaldehyde ( 20.0 g),1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32.32 g), potassium carbonate ( 38.99 g), DME (400 mL) and water (40 mL)was added PdCl₂(dppf) dichloromethane adduct ( 3.45 g) at roomtemperature. Under an argon atmosphere, the reaction mixture was stirredovernight at 90° C., diluted with ethyl acetate at room temperature, andadded to water. The organic layer was washed with water and saturatedbrine, and dried over anhydrous sodium sulfate and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound ( 25.0 g).

¹H NMR (400 MHz, CDCl₃) δ 4.01 (3H, s), 6.97 (1H, d, J = 2.45 Hz), 7.45(1H, d, J = 2.45 Hz), 8.08 (1H, d, J = 8.4 Hz), 8.19 (1H, dd, J = 8.31,1.96 Hz), 9.05 (1H, d, J = 1.47 Hz), 10.09 (1H, s).

F) (1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol

To a solution of 6-(1-methyl-1H-pyrazol-3-yl)nicotinaldehyde ( 25.0 g)in MeOH (375 mL) was added sodium borohydride ( 10.16 g) at 0° C., andthe mixture was stirred at room temperature for 16 hr. To the reactionmixture was added water, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound ( 18.0g).

¹H NMR (500 MHz, CDCl₃) δ 1.81 (1H, brs), 3.98 (3H, s), 4.74 (2H, d, J =4.88 Hz), 6.85 (1H, d, J = 2.44 Hz), 7.41 (1H, d, J = 2.44 Hz), 7.74(1H, dd, J = 8.09, 2.29 Hz), 7.90 (1H, d, J = 7.93 Hz), 8.59 (1H, d, J =1.83 Hz).

G) 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridine Hydrochloride

To a solution of (6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol (18.0 g) in dichloromethane (270 mL) was added TEA ( 11.16 mL) at roomtemperature, and methanesulfonyl chloride ( 7.3 mL) was added dropwiseat 0° C. After stirring at room temperature for 16 hr, water was added,and the reaction mixture was extracted with dichloromethane. The organiclayer was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (ethyl acetate/hexane)to give the title compound ( 13.0 g).

MS: [M+H]⁺ 208.0.

H)1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

A mixture of1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol(100 mg), 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridinehydrochloride (91 mg), PdCl₂ (dppf) (91 mg), 2 M aqueous sodiumcarbonate solution (0.375 mL) and DME (3 mL) was subjected to microwaveirradiation at 100° C. for 1 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The obtainedsolid was crystallized from acetonitrile/MeOH to give the title compound( 45.3 mg).

Example 21,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-oneA) 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-chloropyridine

A mixture of (6-chloropyridin-3-yl)methanol ( 6.50 g), 1H-imidazole (6.16 g), tert-butyldimethylchlorosilane ( 6.82 g) and THF (40 mL) wasstirred at room temperature overnight. The reaction mixture was pouredinto water at room temperature, and the mixture was extracted twice withethyl acetate. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound ( 11.1g).

MS: [M+H]⁺ 258.1.

B)5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-((trimethylsilyl)ethynyl)pyridine

A mixture of 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-chloropyridine( 8.98 g), ethynyltrimethylsilane ( 5.13 g), copper(I) iodide ( 0.33 g),TEA ( 52.9 g), PdCl₂(dppf) dichloromethane adduct ( 1.422 g) andacetonitrile (100 mL) was stirred under a nitrogen atmosphere at 70° C.for 3 hr. The reaction mixture was concentrated under reduced pressure,and the residue was diluted with water and extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(ethyl acetate/hexane) to give the title compound ( 11.1 g).

MS: [M+H]⁺ 320.0.

C) 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-ethynylpyridine

A mixture of5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-((trimethylsilyl)ethynyl)pyridine( 11.1 g), potassium carbonate ( 4.80 g) and MeOH (50 mL) was stirred atroom temperature for 2 hr. The reaction mixture was concentrated underreduced pressure, the residue was diluted with saturated aqueousammonium chloride solution, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give the title compound ( 8.60 g).

MS: [M+H]⁺ 248.0.

D)5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine

To a mixture of5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-ethynylpyridine ( 8.60 g),copper(I) bromide triphenylphosphine adduct ( 3.07 g), methyl iodide (5.43 g) and DMSO (80 mL) was added dropwise a solution of sodium azide (3.39 g) in water (20 mL), and the mixture was stirred under a nitrogenatmosphere at room temperature overnight. The reaction mixture wasdiluted with water at room temperature and the precipitate was collectedby filtration. The isolated precipitate was dissolved in ethanol and theresulting insoluble material was filtered off. The filtrate wasextracted with ethyl acetate and the organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound ( 7.03 g).

MS: [M+H]⁺ 305.3.

E) (1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methanol

A mixture of 1 M solution of tetra-n-butylammonium fluoride in THF (69.3 mL),5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine( 7.03 g) and THF (70 mL) was stirred at room temperature for 18 hr. Thereaction mixture was concentrated, and the residue was purified bysilica gel column chromatography (MeOH/ethyl acetate) to give the titlecompound ( 3.78 g).

¹H NMR (300 MHz, CDCl₃) δ 1.92 (1H, t, J = 5.8 Hz), 4.17 (3H, s), 4.77(2H, d, J = 5.3 Hz), 7.81 (1H, dd, J = 8.1, 2.3 Hz), 8.11 (1H, s), 8.17(1H, d, J = 8.1 Hz), 8.56 (1H, d, J = 1.7 Hz) .

F) 5-(bromomethyl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine

To a mixture of (6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methanol( 0.40 g) and acetonitrile (8 mL) was added phosphorus tribromide ( 0.85g) under ice-cooling, and the mixture was stirred under an argonatmosphere at room temperature for 30 min. To the reaction mixture wasadded saturated aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was washed with ethyl acetate-hexane togive the title compound ( 0.27 g).

MS, found: 253.1, 255.1.

G)1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

To a mixture of1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol( 1.02 g), 5-(bromomethyl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine (0.838 g), 2 M aqueous sodium carbonate solution ( 7.64 mL) and DME (35mL) was added PdCl₂ (dppf) ( 0.093 g) at room temperature. The mixturewas stirred under a nitrogen atmosphere at 80° C. overnight. To themixture was added water at room temperature, and the mixture wasextracted with a mixed solvent of ethyl acetate/THF. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified byHPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1%TFA)). To the obtained fraction was added saturated aqueous sodiumhydrogen carbonate solution, and the mixture was extracted with ethylacetate. The organic layer was dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The obtained solid wascrystallized from ethyl acetate/hexane to give the title compound (289mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.82 (1H, dd, J = 12.7, 4.0 Hz), 2.08-2.25(1H, m), 2.30 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.6 Hz),3.35-3.52 (1H, m), 3.93 (2H, dt, J = 11.0, 5.5 Hz), 4.05-4.15 (4H, m),4.22 (2H, s), 4.44-4.61 (1H, m), 5.24 (1H, d, J = 5.7 Hz), 7.56 (1H, dd,J = 7.9, 2.3 Hz), 7.85 (1H, s), 7.95 (1H, d, J = 8.2 Hz), 8.44 (1H, s),8.48 (1H, d, J = 1.5 Hz), 8.51 (1H, s).

Example 31,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-methylbenzamideA)1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-L-threo-pentitol

To a mixture of1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol( 4.6 g), 1H-imidazole ( 2.66 g) and DMF (46 mL) was addedtert-butyl(chloro)dimethylsilane ( 3.64 mL) at 0° C. The mixture wasstirred at room temperature overnight. To the mixture was added water atroom temperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound ( 5.7 g).

MS, found: 467.2, 469.2.

B)1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol

To a mixture of1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-L-threo-pentitol(25 g), bis(pinacolato)diboron (20.37 g), potassium acetate ( 15.75 g)and toluene (250 mL) was added PdCl₂ (dppf) ( 1.957 g), and the mixturewas stirred under an argon atmosphere at 80° C. overnight. The reactionmixture was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound ( 26.4 g).

MS: [M+H]⁺ 515.4.

C) 4-(bromomethyl)-2-fluorobenzoic Acid

To a mixture of 2-fluoro-4-methylbenzoic acid ( 25.0 g), NBS ( 31.8 g)and trifluorotoluene (50 mL) was added AIBN ( 2.66 g). The mixture wasstirred under a nitrogen atmosphere at 90° C. for 3.5 hr and stirred atroom temperature overnight. To the mixture was added ethyl acetate atroom temperature, and the mixture was washed with water and saturatedbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. To the obtained solid was added isopropylacetate/heptane (⅓). The solid was collected by filtration and washedwith heptane to give the title compound ( 22.2 g). ¹H NMR (300 MHz,DMSO-d₆) δ 4.73 (2H, s), 7.35-7.45 (2H, m), 7.85 (1H, t, J = 7.9 Hz),13.31 (1H, brs).

D) 4-(bromomethyl)-2-fluoro-N-methylbenzamide

To a mixture of 4-(bromomethyl)-2-fluorobenzoic acid ( 27.2 g), acatalytic amount of DMF and ethyl acetate (270 mL) was added dropwiseoxalyl chloride ( 33.3 g) at 0° C. The mixture was stirred at roomtemperature for 1.5 hr and concentrated under reduced pressure. Theresidue was dissolved in THF (270 mL) and added dropwise to a mixture of2 M solution of methylamine in THF ( 57.8 mL), DIPEA (22 mL) and THF(100 mL) at 0° C. The mixture was stirred under a nitrogen atmosphere at0° C. for 2 hr. Water (200 mL) was added dropwise to the mixture at 0°C., and the mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive a yellow solid ( 19.28 g). A mixture of the obtained yellow solid (19.28 g), sodium bromide (68.5 g), lithium bromide ( 57.8 g) and MEK(200 mL) was refluxed for 5 hr. Impurity was filtered off, and thefiltrate was concentrated under reduced pressure. To the obtainedresidue was added ethyl acetate, and the mixture was washed with waterand saturated brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The obtained solid was crystallizedfrom ethyl acetate/hexane to give the title compound ( 15.1 g).

MS, found: 246.0, 248.0.

E)1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

To a mixture of1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol(26 g), 4-(bromomethyl)-2-fluoro-N-methylbenzamide ( 12.43 g), 2 Maqueous sodium carbonate solution (76 mL) and DME (260 mL) was addedPdCl₂(dppf) ( 0.37 g), and the mixture was stirred under an argonatmosphere at 80° C. for 3 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (NH, ethylacetate/hexane) to give the title compound (24 g).

MS: [M+H]⁺ 554.4.

F)1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-methylbenzamide

To a mixture of1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(24 g) and THF (48 mL) was added 1 M solution of tetra-n-butylammoniumfluoride in THF ( 47.7 mL) at room temperature, and the mixture wasstirred at room temperature for 2 hr. To the reaction mixture were addedDME (240 mL) and water (120 mL), and the mixture was stirred. Theprecipitate was collected by filtration and washed with IPE. Theobtained solid ( 17.5 g) was dissolved in a mixture of DMSO (136 mL) andEtOH (34 mL) at 50° C., water (340 mL) was added and the mixture wasfurther stirred at 50° C. for 1 hr. The mixture was stirred at roomtemperature for 2 hr, and the precipitate was collected by filtrationand dried to give the title compound ( 16.8 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.82 (1H, dd, J = 12.8, 4.2 Hz), 2.08-2.22(1H, m), 2.25 (3H, s), 2.52 (3H, s), 2.75 (3H, d, J = 4.5 Hz), 3.11 (1H,t, J = 10.4 Hz), 3.36-3.49 (1H, m), 3.86-3.99 (2H, m), 4.02-4.17 (1H,m), 4.22 (2H, s), 4.44-4.64 (1H, m), 5.24 (1H, d, J = 5.3 Hz), 6.96-7.08(2H, m), 7.55 (1H, t, J = 7.9 Hz), 7.84 (1H, s), 8.16 (1H, dd, J = 4.2,2.6 Hz), 8.44 (1H, s) .

Example 51,5-anhydro-2,3-dideoxy-3-(6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-oneA) 6-(1,3-dimethyl-1H-pyrazol-4-yl)nicotinaldehyde

To a mixture of 6-chloronicotinaldehyde ( 7.0 g), 1,4-dioxane (400 mL)and water (10 mL) were added PdCl₂ (dppf) ( 0.5 g), potassium carbonate( 13.8 g) and1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole( 16.5 g), and the mixture was stirred under a nitrogen atmosphere at110° C. for 16 hr. The mixture was concentrated under reduced pressureand the residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (8.0 g).

MS: [M+H]⁺ 202.1.

B) (1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methanol

To a solution of 6-(1,3-dimethyl-1H-pyrazol-4-yl)nicotinaldehyde ( 8.0g) in MeOH (300 mL) was added sodium borohydride (4.5 g) at 0° C., andthe mixture was stirred at room temperature for 16 hr. To the reactionmixture was added water, and the mixture was extracted withdichloromethane. The organic layer was washed with water and saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to give the title compound ( 6.0 g).The compound was used in the next step without further purification.

MS: [M+H]⁺ 204.1.

C) 5-(chloromethyl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine

To a mixture of (6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methanol (6.0 g) and dichloromethane (150 mL) was added thionyl chloride (10.5 g)at 0° C., and the mixture was stirred at room temperature for 16 hr. Themixture was neutralized with saturated aqueous sodium hydrogen carbonatesolution and extracted with dichloromethane. The organic layer waswashed with saturated brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/petroleum ether) to give thetitle compound ( 4.5 g).

MS: [M+H]⁺222.1.

D)1,5-anhydro-2,3-dideoxy-3-(6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

A mixture of1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol(125 mg), 5-(chloromethyl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine (97mg), 2 M aqueous sodium carbonate solution ( 0.468 mL), DME (3 mL) andPdCl₂(dppf) ( 11.42 mg) was subjected to microwave irradiation at 100°C. for 1 hr. To the mixture was added water at room temperature, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by HPLC(L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1%TFA)). The obtained fraction was filtered through StratoSpheres SPE(PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtainedsolid was crystallized from MeOH/hexane to give the title compound (43mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.82 (1H, dt, J = 12.7, 1.4 Hz), 2.07-2.26(1H, m), 2.31 (3H, s), 2.40 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4Hz), 3.32-3.49 (1H, m), 3.78 (3H, s), 3.88-3.99 (2H, m), 4.02-4.20 (3H,m), 4.39-4.62 (1H, m), 5.08-5.35 (1H, m), 7.48 (2H, s), 7.83 (1H, s),8.11 (1H, s), 8.41 (2H, d, J = 11.7 Hz).

Example 61,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

A mixture of1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol(150 mg), 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (101mg), 2 M aqueous sodium carbonate solution ( 0.562 mL), PdCl₂ (dppf) (13.71 mg) and DME (4 mL) was subjected to microwave irradiation at 100°C. for 1 hr. To the mixture was added water at room temperature, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by HPLC(L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1%TFA)). The obtained fraction was filtered through StratoSpheres SPE(PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtainedsolid was crystallized from MeOH/hexane to give the title compound (64.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.82 (1H, dd, J = 12.7, 4.0 Hz), 2.12-2.23(1H, m), 2.30 (3H, s), 2.53 (3H, s), 3.04-3.15 (1H, m), 3.42 (1H, t, J =11.0 Hz), 3.85-3.95 (5H, m), 4.05-4.19 (3H, m), 4.45-4.61 (1H, m), 5.24(1H, d, J = 4.5 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.54 (1H, d, J = 8.0 Hz),7.81 (1H, s), 7.93 (1H, d, J = 0.8 Hz), 8.21 (1H, s), 8.36 (1H, d, J =1.5 Hz), 8.43 (1H, s) .

Example 101,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitolA) 2-amino-5-bromo-4-methylbenzoic Acid

To a mixture of 2-amino-4-methylbenzoic acid ( 6.14 g) and DMSO (60 mL)was added hydrobromic acid (48% v/v, 23 mL) at 0° C., and the mixturewas stirred at room temperature overnight. To the reaction mixture wasadded water (150 mL) and the mixture was stirred for 30 min. Theprecipitate was collected by filtration, washed with water and dried togive the title compound ( 9.04 g).

MS, found: 230.0, 232.0.

B) 2-amino-5-bromo-3-chloro-4-methylbenzoic Acid

To a mixture of 2-amino-5-bromo-4-methylbenzoic acid ( 9.04 g) andacetonitrile (180 mL) was added NCS ( 7.35 g) at room temperature. Themixture was stirred at room temperature overnight. The precipitate wascollected by filtration, washed with a small amount of ethyl acetate anddried under reduced pressure to give the title compound ( 5.59 g).

MS, found: 264.0, 266.0.

C)3-(amino-5-bromo-3-chloro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol

To a mixture of 2-amino-5-bromo-3-chloro-4-methylbenzoic acid (5 g),3-amino-1,5-anhydro-2,3-dideoxy-L-threo-pentitol hydrochloride ( 2.9 g),HATU ( 8.63 g) and DMF (100 mL) was added TEA ( 6.59 mL) at roomtemperature, and the mixture was stirred overnight. To the reactionmixture was added 5% aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give the title compound ( 8.75g). Further purification was not performed and the compound was used inthe next step.

MS, found: 363.0, 365.0.

D)1,5-anhydro-3-(6-bromo-8-chloro-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

A mixture of3-((2-amino-5-bromo-3-chloro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol( 8.75 g) and N,N-dimethylformamide dimethyl acetal (80 mL) was stirredunder a nitrogen atmosphere at 90° C. for 2 hr. The reaction mixture wasconcentrated under reduced pressure and the obtained solid wascrystallized from ethyl acetate/hexane to give the title compound ( 6.52g).

MS, found: 373.0, 375.0.

E)1,5-anhydro-3-(8-chloro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

To a mixture of1,5-anhydro-3-(6-bromo-8-chloro-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol( 3.5 g), bis(pinacolato)diboron ( 2.85 g), potassium acetate ( 2.76 g)and toluene (60 mL) was added Pd(PPh₃)₂Cl₂ ( 0.329 g), and the mixturewas stirred under a nitrogen atmosphere at 110° C. overnight. To thereaction mixture was added 5% aqueous sodium hydrogen carbonate solutionat room temperature, and the mixture was extracted with ethylacetate/THF mixed solvent. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained solid was washed withIPE to give the title compound ( 2.37 g). Further purification was notperformed and the compound was used in the next step.

MS: [M+H]⁺ 421.2.

F)1,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

A mixture of1,5-anhydro-3-(8-chloro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(150 mg), 4-(bromomethyl)-2-fluoro-N-methylbenzamide (114 mg), 2 Maqueous sodium carbonate solution ( 0.535 mL), PdCl₂(dppf) ( 13.04 mg)and DME (5 mL) was subjected to microwave irradiation at 100° C. for 1hr. To the mixture was added water at room temperature, and the mixturewas extracted with ethyl acetate/THF mixed solvent. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified byHPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1%TFA)). The obtained fraction was filtered through StratoSpheres SPE(PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtainedsolid was crystallized from acetonitrile/hexane to give the titlecompound (89 mg).

Example 171,5-anhydro-3-(6-(4-carboxybenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitolA)1,5-anhydro-2,3-dideoxy-3-(6-(4-(methoxycarbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

A mixture of1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol( 8.58 g), methyl 4-(chloromethyl)benzoate ( 3.75 g), PdCl₂(dppf) ( 0.62g), sodium carbonate ( 4.49 g), water (20 mL) and DME (120 mL) wasstirred under an argon atmosphere at 80° C. for 10 hr. To the mixturewas added water at room temperature, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (NH, ethyl acetate/hexane) to give the title compound (4.5 g).

MS: [M+H]⁺ 423.3.

B)1,5-anhydro-3-(6-(4-carboxybenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

To a mixture of1,5-anhydro-2,3-dideoxy-3-(6-(4-(methoxycarbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol( 4.5 g), THF (45 mL) and MeOH (45 mL) was added 2 M aqueous sodiumhydroxide solution (16 mL), and the mixture was stirred under a nitrogenatmosphere at room temperature overnight, and further stirred at 45° C.for 4 hr. The mixture was cooled to room temperature, neutralized with 2M hydrochloric acid and concentrated under reduced pressure. To theresidue was added ethyl acetate, and the mixture was concentrated againunder reduced pressure. The precipitated solid was collected byfiltration, washed with water, and dried to give the title compound (3.95 g).

¹H NMR (300 MHz, DMSO-d₆) δ 1.77-1.90 (1H, m), 2.11-2.32 (4H, m),2.45-2.54 (3H, m), 3.06-3.16 (1H, m), 3.37-3.48 (1H, m), 3.87-3.99 (2H,m), 4.02-4.17 (1H, m), 4.24 (2H, s), 4.47-4.64 (1H, m), 5.25 (1H, d, J =5.7 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.83 (1H, s), 7.87 (2H, d, J = 8.3Hz), 8.43 (1H, s), 12.83 (1H, brs) .

Example 181,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(methylcarbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

To a mixture of1,5-anhydro-3-(6-(4-carboxybenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(60 mg), methylamine hydrochloride ( 19.84 mg), DIPEA (76 mg) and DMA (2mL) was added HATU (84 mg) at room temperature and the mixture wasstirred for 10 hr. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (NH, ethyl acetate/hexane) to give the titlecompound ( 38.6 mg).

Example 191,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(Synonym)4-((8-chloro-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-4-oxo-3,4-dihydrobenzod1,2,3triazin-6-yl)methyl)-2-fluoro-N-methylbenzamideA)1,5-anhydro-3-(6-bromo-8-chloro-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

To a mixture of3-((2-amino-5-bromo-3-chloro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol( 4.59 g) and 2 M hydrochloric acid (38 mL) was added dropwise asolution of sodium nitrite ( 0.91 g) in water (10 mL) at 0° C., and themixture was stirred at room temperature for 3 hr. The reaction mixturewas neutralized with 2 M aqueous sodium hydroxide solution at 0° C., andthe precipitate was collected by filtration and washed with water togive the title compound ( 1.9 g). Further purification was not performedand the compound was used in the next step.

MS, found: 374.1, 376.1.

B)1,5-anhydro-3-(8-chloro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

To a mixture of1,5-anhydro-3-(6-bromo-8-chloro-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol( 1.89 g), bis(pinacolato)diboron ( 1.54 g), potassium acetate ( 1.49 g)and toluene (60 mL) was added Pd(PPh₃)₂Cl₂ ( 0.33 g), and the mixturewas stirred under a nitrogen atmosphere at 110° C. overnight. To thereaction mixture was added 5% aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate/THF mixedsolvent. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The obtained solid was crystallized from ethylacetate/hexane to give the title compound (609 mg). Further purificationwas not performed and the compound was used in the next step.

MS: 422.2.

C)1,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(Synonym)4-((8-chloro-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-4-oxo-3,4-dihydrobenzod1,2,3triazin-6-yl)methyl)-2-fluoro-N-methylbenzamide

A mixture of1,5-anhydro-3-(8-chloro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(180 mg), 4-(bromomethyl)-2-fluoro-N-methylbenzamide (137 mg), 2 Maqueous sodium carbonate solution ( 0.640 mL), PdCl₂(dppf) ( 15.62 mg)and DME (5 mL) was subjected to microwave irradiation at 100° C. for 1hr. To the mixture was added water at room temperature, and the mixturewas extracted with ethyl acetate/THF mixed solvent. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified byHPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1%TFA)). The obtained fraction filtered through StratoSpheres SPE (PL-HCO3MP-Resin) and concentrated under reduced pressure. The obtained solidwas crystallized from acetonitrile/hexane to give the title compound (28mg).

¹H NMR (400 MHz, CD₃OD) δ 1.98-2.07 (1H, m), 2.29 (1H, qd, J = 12.6, 4.8Hz), 2.54 (3H, s), 2.90 (4H, s), 3.30 (1H, dt, J = 3.3, 1.5 Hz), 3.59(1H, td, J = 12.0, 2.1 Hz), 4.01-4.13 (2H, m), 4.29 (1H, td, J = 10.0,5.1 Hz), 4.35 (2H, s), 4.86 (1H, s), 5.09 (1H, ddd, J = 12.1, 9.9, 4.6Hz), 7.02 (1H, d, J = 12.0 Hz), 7.08 (1H, dd, J = 7.9, 1.6 Hz), 7.70(1H, t, J = 7.8 Hz), 8.01 (1H, s).

Example 211,5-anhydro-2,3-dideoxy-3-(8-fluoro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitolA) 2-amino-5-bromo-3-fluoro-4-methylbenzoic Acid

To a mixture of 2-amino-3-fluoro-4-methylbenzoic acid (10 g) and DMF(200 mL) was added NBS ( 12.63 g) at 0° C. The mixture was stirred at 0°C. for 1 hr and further stirred at room temperature overnight. To themixture was added water (300 mL) at room temperature, and theprecipitated solid was collected by filtration, washed with water anddried under reduced pressure to give the title compound ( 14.4 g).

MS, found: 248.0, 250.0.

B)3-(amino-5-bromo-3-fluoro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol

To a mixture of 2-amino-5-bromo-3-fluoro-4-methylbenzoic acid (10 g),3-amino-1,5-anhydro-2,3-dideoxy-L-threo-pentitol hydrochloride ( 6.19g), HATU ( 18.4 g) and DMF (150 mL) was added TEA (14 mL) at roomtemperature and the mixture was stirred overnight. To the reactionmixture was added 5% aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained solid was crystallizedfrom ethyl acetate to give the title compound ( 3.57 g).

MS, found: 347.1, 349.1.

C)1,5-anhydro-3-(6-bromo-8-fluoro-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

A mixture of3-((2-amino-5-bromo-3-fluoro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol( 14.1 g) and N,N-dimethylformamide dimethyl acetal (50 mL) was stirredunder a nitrogen atmosphere at 90° C. for 2 hr. The reaction mixture wasconcentrated under reduced pressure and the obtained solid wascrystallized from ethyl acetate/hexane to give the title compound ( 8.36g).

MS, found: 357.1, 359.1.

D)1,5-anhydro-2,3-dideoxy-3-(8-fluoro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol

To a mixture of1,5-anhydro-3-(6-bromo-8-fluoro-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol( 5.0 g), bis(pinacolato)diboron ( 4.27 g), potassium acetate ( 4.12 g)and toluene (60 mL) was added Pd(PPh₃)₂Cl₂ ( 0.329 g), and the mixturewas stirred under a nitrogen atmosphere at 110° C. overnight. To thereaction mixture was added 5% aqueous sodium hydrogen carbonate solutionat room temperature, and the mixture was extracted with ethylacetate/THF mixed solvent. The organic layer was washed with saturatedbrine and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained solid was washed withIPE to give the title compound ( 3.47 g). Further purification was notperformed and the compound was used in the next step.

MS: [M+H]⁺ 405.3.

E)1,5-anhydro-2,3-dideoxy-3-(8-fluoro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

A mixture of1,5-anhydro-2,3-dideoxy-3-(8-fluoro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol(150 mg), 4-(bromomethyl)-2-fluoro-N-methylbenzamide (119 mg), 2 Maqueous sodium carbonate solution ( 0.557 mL), PdCl₂(dppf) ( 13.58 mg)and DME (5 mL) was subjected to microwave irradiation at 100° C. for 1hr. To the mixture was added water at room temperature, and the mixturewas extracted with ethyl acetate/THF mixed solvent. The organic layerwas washed with saturated brine, dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was purified byHPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1%TFA)). The obtained fraction was filtered through StratoSpheres SPE(PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtainedsolid was crystallized from MeOH/hexane to give the title compound (28.8 mg).

Example 601,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitolA)1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methoxycarbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

To a mixture of1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol( 6.75 g), methyl 4-(bromomethyl)-2-fluorobenzoate ( 5.00 g), 2 Maqueous sodium carbonate solution ( 25.3 mL) and DME (100 mL) was addedPdCl₂(dppf) ( 0.62 g), and the mixture was stirred under a nitrogenatmosphere at 80° C. for 2 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (NH, ethylacetate/hexane) and the obtained solid was crystallized from ethylacetate/hexane to give the title compound ( 3.44 g).

MS: [M+H]⁺ 441.2.

B)1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

To a mixture of1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methoxycarbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol( 4.06 g), THF (50 mL) and MeOH (25 mL) was added 2 M aqueous sodiumhydroxide solution (10 mL), and the mixture was stirred at 50° C.overnight. The mixture was cooled to room temperature, neutralized with2 M hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The obtainedsolid was crystallized from ethyl acetate/hexane to give the titlecompound ( 3.41 g).

Example 661,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(2-methoxyethyl)benzamide

To a mixture of1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(110 mg), 2-methoxyethanamine ( 38.7 mg), DIPEA ( 0.18 mL) and DMA (4mL) was added HATU (147 mg) at room temperature. The mixture was stirredat room temperature overnight. Water was added to the mixture, and theprecipitated solid was collected by filtration, washed with water anddried under reduced pressure to give the title compound (94 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.74-1.87 (1H, m), 2.11-2.31 (4H, m), 2.52(3H, brs), 3.11 (1H, t, J = 10.6 Hz), 3.26 (3H, s), 3.36-3.46 (5H, m),3.93 (2H, dt, J = 11.0, 5.1 Hz), 3.99-4.14 (1H, m), 4.22 (2H, s),4.41-4.64 (1H, m), 5.24 (1H, d, J = 5.3 Hz), 6.94-7.10 (2H, m), 7.54(1H, t, J = 7.9 Hz), 7.84 (1H, s), 8.21 (1H, d, J = 3.0 Hz), 8.44 (1H,s).

Example 711,5-anhydro-3-(6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(Synonym)6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-oneA)1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

To a mixture of1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol(1500 mg), 2-chloro-5-(chloromethyl)pyridine (729 mg), 2 M aqueoussodium carbonate solution ( 5.62 mL) and DME (50 mL) was addedPdCl₂(dppf) ( 0.137 g), and the mixture was stirred under a nitrogenatmosphere at 80° C. overnight. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (Diol, ethylacetate/hexane) to give the title compound (952 mg).

MS: [M+H]⁺ 400.2.

B)1,5-anhydro-3-(6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(Synonym)6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

A mixture of1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(140 mg),1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(130 mg), PdCl₂(Amphos)₂ ( 23.55 mg), 2 M aqueous sodium carbonatesolution ( 0.525 mL) and DME (4 mL) was subjected to microwaveirradiation at 110° C. for 1 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile(containing 0.1% TFA)). The obtained fraction was filtered throughStratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reducedpressure. The obtained solid was crystallized from ethyl acetate/hexaneto give the title compound (39 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.35-0.42 (2H, m), 0.51-0.58 (2H, m),1.21-1.28 (1H, m), 1.82 (1H, dd, J = 12.3, 3.6 Hz), 2.06-2.26 (1H, m),2.30 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.42 (1H, t, J =11.0 Hz), 3.87-4.13 (6H, m), 4.19 (2H, s), 4.53 (1H, brs), 7.55-7.71(2H, m), 7.83 (1H, s), 8.01 (1H, s), 8.36 (1H, s), 8.40-8.46 (2H, m).

Example 721,5-anhydro-3-(6-((6-(1-tert-butyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(Synonym)6-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

A mixture of1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(140 mg),1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(131 mg), PdCl₂(Amphos)₂ ( 23.55 mg) and 2 M aqueous sodium carbonatesolution ( 0.525 mL) and DME (4 mL) was subjected to microwaveirradiation at 110° C. for 1 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile(containing 0.1% TFA)). The obtained fraction was filtered throughStratoSpheres SPE (PL-HCO3 MP-Resin), and concentrated under reducedpressure. The obtained solid was crystallized from ethyl acetate/hexaneto give the title compound ( 55.4 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.55 (9H, s), 1.70-1.90 (1H, m), 2.05-2.24(1H, m), 2.30 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.42(1H, t, J = 11.0 Hz), 3.83-4.19 (5H, m), 4.43-4.63 (1H, m), 5.24 (1H, d,J = 5.3 Hz), 7.45 (1H, dd, J = 8.1, 2.1 Hz), 7.60 (1H, d, J = 7.9 Hz),7.80 (1H, s), 7.97 (1H, s), 8.31-8.45 (3H, m).

Example 731,5-anhydro-2,3-dideoxy-3-(6-((6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-((6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethylquinazolin-4(3H)-one

A mixture of1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(140 mg),1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(132 mg), PdCl₂(Amphos)₂ ( 23.55 mg), 2 M aqueous sodium carbonatesolution ( 0.525 mL) and DME (4 mL) was subjected to microwaveirradiation at 110° C. for 1 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile(containing 0.1% TFA)). The obtained fraction was filtered throughStratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reducedpressure. The obtained solid was crystallized from ethyl acetate/hexaneto give the title compound ( 45.2 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.71-1.92 (1H, m), 2.08-2.34 (4H, m), 2.53(3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.23 (3H, s), 3.34-3.50 (1H, m),3.71 (2H, t, J = 5.1 Hz), 3.87-3.97 (2H, m), 4.04-4.14 (1H, m), 4.22(2H, s), 4.32 (2H, t, J = 5.3 Hz), 4.42-4.69 (1H, m), 4.99-5.85 (1H, m),7.60-7.76 (2H, m), 7.84 (1H, s), 8.07 (1H, s), 8.35 (1H, s), 8.42-8.48(2H, m) .

Example 741,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

A mixture of1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(140 mg),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole(145 mg), PdCl₂(Amphos)₂ ( 23.55 mg), 2 M aqueous sodium carbonatesolution ( 0.525 mL) and DME (4 mL) was subjected to microwaveirradiation at 110° C. for 1 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile(containing 0.1% TFA)). The obtained fraction was filtered throughStratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reducedpressure. The obtained solid was crystallized from ethyl acetate/hexaneto give the title compound (75 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.72-1.72 (1H, m), 2.08-2.34 (4H, m), 2.53(3H, s), 3.11 (1H, t, J = 10.2 Hz), 3.42 (1H, t, J = 11.0 Hz), 3.93 (2H,dt, J = 10.9, 5.3 Hz), 4.03-4.14 (1H, m), 4.18 (2H, s), 4.44-4.61 (1H,m), 5.13-5.28 (3H, m), 7.49 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H, d, J =7.9 Hz), 7.82 (1H, s), 8.11 (1H, s), 8.36-8.45 (3H, m).

Example 751,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

A mixture of1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(140 mg),1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(146 mg), PdCl₂(Amphos)₂ ( 23.55 mg), 2 M aqueous sodium carbonatesolution ( 0.525 mL) and DME (4 mL) was subjected to microwaveirradiation at 110° C. for 1 hr. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile(containing 0.1% TFA)). The obtained fraction was filtered throughStratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reducedpressure. The obtained solid was crystallized from ethyl acetate/hexaneto give the title compound (42 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.75-1.88 (1H, m), 1.96-2.03 (4H, m),2.10-2.25 (1H, m), 2.31 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4Hz), 3.37-3.53 (3H, m), 3.88-4.13 (6H, m), 4.23 (2H, s), 4.42-4.58 (2H,m), 7.72-7.85 (3H, m), 8.11 (1H, s), 8.43-8.51 (3H, m).

Example 811,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(((2R)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(((R)-tetrahydrofuran-2-yl)methyl)benzamide

To a mixture of1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(90 mg), (S)-(tetrahydrofuran-2-yl)methanamine ( 28.2 mg), DIPEA ( 0.144mL) and DMA (3 mL) was added HATU (120 mg) at room temperature. Themixture was stirred at room temperature overnight. To the mixture wasadded water at room temperature, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(NH, MeOH/ethyl acetate) and the obtained solid was crystallized fromethyl acetate/IPE/hexane to give the title compound ( 54.9 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 1.49-1.65 (1H, m), 1.73-1.93 (4H, m),2.09-2.23 (1H, m, J = 4.2 Hz), 2.25 (3H, s), 2.52 (3H, brs), 3.11 (1H,t, J 10.4 Hz), 3.26-3.30 (1H, m), 3.35-3.50 (1H, m), 3.56-3.66 (2H, m),3.72-3.80 (1H, m), 3.89-4.01 (3H, m), 4.02-4.16 (1H, m), 4.22 (2H, s),4.38-4.74 (1H, m), 5.24 (1H, d, J = 5.3 Hz), 6.98-7.06 (2H, m), 7.53(1H, t, J = 7.9 Hz), 7.85 (1H, s), 8.21 (1H, d, J = 3.0 Hz), 8.44 (1H,s).

Example 821,5-anhydro-2,3-dideoxy-3-(6-((6-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitolA)1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol

A mixture of1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(150 mg), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(166 mg), PdCl₂ (dppf) ( 25.2 mg), 2 M aqueous sodium carbonate solution( 0.563 mL) and DME (4 mL) was subjected to microwave irradiation at110° C. for 1 hr. To the mixture was added water at room temperature,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by HPLC(L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1%TFA)). The obtained fraction was filtered through StratoSpheres SPE(PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtainedsolid was crystallized from acetonitrile/MeOH to give the title compound( 43.0 mg).

MS: [M+H]⁺ 432.2.

B)1,5-anhydro-2,3-dideoxy-3-(6-((6-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

To a mixture of1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol( 39.5 mg) and DMF (2 mL) was added 60% sodium hydride (10 mg) at roomtemperature. The reaction mixture was stirred under a nitrogenatmosphere at room temperature for 30 min, and2-chloro-N,N-dimethylacetamide (20 mg) was added. After stirring at roomtemperature overnight, to the mixture was added water, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. The residue was purified by HPLC (L-Column 2ODS, mobile phase: water/acetonitrile (containing 10 mM ammoniumbicarbonate)). The obtained fraction was concentrated under reducedpressure to give the title compound ( 10.9 mg).

¹H NMR (300 MHz, CD₃OD) δ 1.90-1.99 (1H, m), 2.27-2.39 (4H, m), 2.57(3H, s), 2.97 (3H, s), 3.13 (3H, s), 3.23 (1H, dd, J = 11.0, 10.2 Hz),3.53 (1H, d, J= 1.9 Hz), 3.97-4.11 (2H, m), 4.16-4.29 (3H, m), 4.48-4.66(1H, m), 5.17 (2H, s), 6.92 (1H, d, J = 0.8 Hz), 7.50-7.60 (2H, m), 7.93(1H, s), 8.01 (1H, d, J =0.8 Hz), 8.13 (1H, s), 8.26-8.32 (2H, m).

Example 851,5-anhydro-2,3-dideoxy-3-(6-(4-((2-ethoxyethyl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)N-(2-ethoxyethyl)-2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide

To a mixture of1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(90 mg), 2-ethoxyethanamine ( 28.2 mg), DIPEA ( 0.14 mL) and DMA (3 mL)was added HATU (120 mg) at room temperature. The mixture was stirred atroom temperature overnight. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (NH, MeOH/ethylacetate) and the obtained solid was crystallized from ethylacetate/hexane to give the title compound ( 71.4 mg). ¹H NMR (300 MHz,DMSO-d₆) δ 1.10 (3H, t, J = 7.0 Hz), 1.77-1.87 (1H, m), 2.08-2.30 (4H,m), 2.52 (3H, brs), 3.11 (1H, t, J = 10.4 Hz), 3.35-3.48 (7H, m), 3.93(2H, dt, J = 10.9, 5.3 Hz), 4.00-4.16 (1H, m), 4.22 (2H, s), 4.42-4.67(1H, m), 5.24 (1H, d, J = 5.3 Hz), 6.99-7.06 (2H, m), 7.55 (1H, t, J =8.0 Hz), 7.85 (1H, s), 8.16-8.24 (1H, m), 8.44 (1H, s).

Example 861,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((3-methoxypropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Synonym)2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(3-methoxypropyl)benzamide

To a mixture of1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(90 mg), 3-methoxypropan-1-amine ( 37.6 mg), DIPEA ( 0.14 mL) and DMA (3mL) was added HATU (120 mg) at room temperature. The mixture was stirredat room temperature overnight. To the mixture was added water at roomtemperature, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (NH, MeOH/ethylacetate) and the obtained solid was crystallized from ethylacetate/IPE/hexane to give the title compound ( 55.7 mg) .

¹H NMR (300 MHz, DMSO-d₆) δ 1.63-1.87 (3H, m), 2.09-2.31 (4H, m), 2.52(3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.24-3.53 (8H, m), 3.93 (2H, dt, J =10.9, 5.3 Hz), 4.01-4.15 (1H, m), 4.22 (2H, s), 4.39-4.71 (1H, m), 5.24(1H, d, J = 5.3 Hz), 6.98-7.06 (2H, m), 7.53 (1H, t, J = 7.8 Hz), 7.84(1H, s), 8.18-8.26 (1H, m), 8.44 (1H, s).

Example 871,5-anhydro-3-(6-(4-(cyclopropylcarbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(Synonym)N-cyclopropyl-2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide

To a mixture of1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(90 mg), cyclopropanamine ( 24.10 mg), DIPEA ( 0.14 mL) and DMA (3 mL)was added HATU (120 mg) at room temperature. The mixture was stirred atroom temperature for 15 hr. To the mixture was added water, and theprecipitated solid was collected by filtration, washed with water andIPE and dried under reduced pressure to give the title compound (83 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 0.46-0.59 (2H, m), 0.61-0.70 (2H, m),1.73-1.89 (1H, m), 2.10-2.30 (4H, m), 2.52 (3H, s), 2.76-2.86 (1H, m),3.11 (1H, t, J = 10.4 Hz), 3.35-3.52 (1H, m), 3.93 (2H, dt, J = 10.8,5.2 Hz), 4.03-4.14 (1H, m), 4.21 (2H, s), 4.42-4.66 (1H, m), 5.24 (1H,d, J = 5.7 Hz), 6.97-7.04 (2H, m), 7.47 (1H, t, J = 7.9 Hz), 7.83 (1H,s), 8.28 (1H, d, J = 3.8 Hz), 8.43 (1H, s).

Example 921,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Diastereomeric Mixture) A) 2-fluoro-4-(hydroxymethyl)-N-methylbenzamide

To a mixture of 4-(bromomethyl)-2-fluoro-N-methylbenzamide (3 g) and DMF(12 mL) was added potassium acetate ( 1.436 g), and the mixture wasstirred at room temperature for 3 hr. Potassium carbonate ( 3.37 g) andmethanol (4 mL) were added and the mixture was stirred at roomtemperature for 3 hr. To the mixture was added water, and the mixturewas extracted 7 times with mixture of ethyl acetate and 2-propanol. Theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound ( 2.0 g).

MS: [M+H]⁺ 184.2.

B) 2-fluoro-4-formyl-N-methylbenzamide

To a mixture of 2-fluoro-4-(hydroxymethyl)-N-methylbenzamide (100 mg)and toluene (5 mL) was added manganese dioxide (237 mg) at 70° C. Themixture was stirred at 70° C. for 2 hr, and the reaction mixture waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound (74 mg).

¹H NMR (300 MHz, DMSO-d₆) δ 2.79 (3H, d, J = 4.5 Hz), 7.68-7.90 (3H, m),8.48 (1H, brs), 10.03 (1H, d, J = 1.5 Hz).

C)1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-iodo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

A mixture of1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-L-threo-pentitol( 1.0 g), trans-1,2-bis(methylamino)cyclohexane (30 mg), copper(I)iodide (20 mg), sodium iodide (962 mg) and acetonitrile was subjected tomicrowave irradiation at 130° C. for 24 hr. To the mixture was addedaqueous ammonia at room temperature, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate/hexane) to give the title compound (860mg).

MS: [M+H]⁺ 515.3.

D)1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-((3-fluoro-4-(methylcarbamoyl)phenyl)(hydroxy)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Diastereomic Mixture)

To a solution of1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-iodo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(760 mg) in THF was added dropwise 1.3 M THF solution ( 1.136 mL) ofisopropylmagnesium chloride-lithium chloride complex under an argonatmosphere at -10° C. The reaction mixture was stirred at -10° C. for 30min and 2-fluoro-4-formyl-N-methylbenzamide (268 mg) was added. To themixture was added saturated aqueous ammonium chloride solution, and themixture was extracted with ethyl acetate. The organic layer wasseparated, washed with water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (NH, ethyl acetate/hexane)to give the title compound (220 mg).

MS: [M+H]⁺ 570.4.

E)1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Diastereomeric Mixture)

To a mixture of1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-((3-fluoro-4-(methylcarbamoyl)phenyl)(hydroxy)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(diastereomeric mixture) (220 mg) and toluene was added(diethylamino)sulfur trifluoride ( 0.0663 mL) under an argon atmosphereat -40° C. The mixture was stirred at -40° C. for 1 hr, saturatedaqueous sodium hydrogen carbonate was added, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) to give the titlecompound (174 mg).

MS: [M+H]⁺ 572.4.

F)1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Diastereomeric Mixture)

To a mixture of1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(25 mg) and THF was added 1 M tetra-N-butylammonium fluoride THFsolution ( 0.0568 mL) at room temperature, and the mixture was stirredat room temperature for 1 hr. To the reaction mixture were added DME andwater, and the mixture was stirred. The precipitate was collected byfiltration and dried to give the title compound ( 12.2 mg).

Example 931,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Epimer of Example 94) A)1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Stereoisomer: Retention Time Short)

1,5-Anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(diastereomeric mixture) (177 mg) obtained in step E of Example 92 wasseparated by SFC (column: CHIRALPAK AD-H, 20 mmID×250 mmL, mobile phase:carbon dioxide/EtOH = 740/260, flow rate: 50 mL/min) to give the titlecompound (69 mg) having a shorter retention time (tR1).

100%ee (SFC (column: CHIRALPAK IC, 4.6 mmID×250 mmL, mobile phase:carbon dioxide/EtOH = 740/260, flow rate: 2.5 mL/min, retention time:3.98 min))

MS: [M+H]⁺ 572.3.

B)1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Epimer of Example 94)

The title compound was obtained by a method similar to that in step F ofExample 92.

Example 941,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Epimer of Example 93) A)1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Stereoisomer: Retention Time Long)

1,5-Anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(diastereomeric mixture) (177 mg) obtained in step E of Example 92 wasseparated by SFC (column: CHIRALPAK AD-H, 20 mmID×250 mmL, mobile phase:carbon dioxide/EtOH = 740/260, flow rate: 50 mL/min) to give the titlecompound (74 mg) having a longer retention time (tR2).

100%ee (SFC (column: CHIRALPAK IC, 4.6 mmID×250 mmL, mobile phase:carbon dioxide/EtOH = 740/260, flow rate: 2.5 mL/min, retention time:4.65 min))

MS: [M+H]⁺ 572.3.

B)1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(Epimer of Example 93)

The title compound was obtained by a method similar to that in step F ofExample 92.

The compounds of Examples are shown in the following Tables. In theTables, MS means measured values. The compounds of Examples 4, 7-9,11-16, 20, 22-59, 61-65, 67-70, 76-80, 83, 84 and 88-91 in the followingTables were produced by the methods shown in the above-mentionedExamples or a method analogous thereto.

TABLE 1-1 Ex. No. IUPAC name structural formula salt MS 11,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

446.3 21,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(synonym)3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

447.1 31,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(synonym)2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-methylbenzamide

440.2 41,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(6-methylpyridazin-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

457.2

TABLE 1-2 Ex. No. IUPAC name structural formula salt MS 51,5-anhydro-2,3-dideoxy-3-(6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(synonym)6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

460.3 61,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(synonym)3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

446.3 71,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-methylpyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

380.3 81,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

446.2

TABLE 1-3 Ex. No. IUPAC name structural formula salt MS 91,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

445.3 101,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

460.2 111,5-anhydro-3-(8-chloro-7-methyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

466.2 121,5-anhydro-3-(8-chloro-6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

480.2 131,5-anhydro-3-(8-chloro-7-methyl-6-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

466.2

TABLE 1-4 Ex. No. IUPAC name structural formula salt MS 141,5-anhydro-3-(8-chloro-7-methyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

467.2 151,5-anhydro-3-(8-chloro-7-methyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

466.2 161,5-anhydro-3-(8-chloro-7-methyl-6-((6-methylpyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

400.2 171,5-anhydro-3-(6-(4-carboxybenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

407.1 181,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(methylcarbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

422.2

TABLE 1-5 Ex. No. IUPAC name structural formula salt MS 191,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(synonym)4-((8-chloro-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)methyl)-2-fluoro-N-methylbenzamide

461.2 201,5-anhydro-3-(8-chloro-7-methyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

467.2 211,5-anhydro-2,3-dideoxy-3-(8-fluoro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

444.2 221,5-anhydro-2,3-dideoxy-3-(8-fluoro-7-methyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

450.2

TABLE 1-6 Ex. No. IUPAC name structural formula salt MS 231,5-anhydro-2,3-dideoxy-3-(6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-8-fluoro-7-methyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

464.2 241,5-anhydro-2,3-dideoxy-3-(8-fluoro-7-methyl-6-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

449.1 251,5-anhydro-2,3-dideoxy-3-(6-(4-((3,3-difluorocyclobutyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

498.2 261,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-((3-methyloxetan-3-yl)carbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

478.2 271,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(oxetan-3-ylcarbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

464.2

TABLE 1-7 Ex. No. IUPAC name structural formula salt MS 281,5-anhydro-2,3-dideoxy-3-(6-(4-(ethylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

436.2 291,5-anhydro-3-(6-(4-((cyclopropylmethyl)carbamoyl)-benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

462.2 301,5-anhydro-2,3-dideoxy-3-(6-(4-((2-(dimethylamino)-2-oxoethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

493.2 311,5-anhydro-2,3-dideoxy-3-(6-(4-((2-methoxy-2-methylpropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

494.3 321,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(tetrahydro-2H-pyran-4-ylcarbamoyl)benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol

492.3

TABLE 1-8 Ex. No. IUPAC name structural formula salt MS 331,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(tetrahydrofuran-3-ylcarbamoyl)benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol

478.2 341,5-anhydro-2,3-dideoxy-3-(6-(4-((3-fluoropropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

468.2 351,5-anhydro-2,3-dideoxy-3-(6-(4-((1-(difluoromethyl)-cyclopropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

498.2 361,5-anhydro-2,3-dideoxy-3-(6-(4-(isopropylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

450.2 371,5-anhydro-2,3-dideoxy-3-(6-(4-((2-fluoroethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

454.2

TABLE 1-9 Ex. No. IUPAC name structural formula salt MS 381,5-anhydro-2,3-dideoxy-3-(6-(4-((3-methoxypropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

480.2 391,5-anhydro-2,3-dideoxy-3-(6-(4-((2-hydroxy-2-methylpropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

480.2 401,5-anhydro-2,3-dideoxy-3-(6-(4-((3-hydroxyazetidin-1-yl)carbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

464.2 411,5-anhydro-2,3-dideoxy-3-(6-(4-((3-methoxyazetidin-1-yl)carbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

478.2 421,5-anhydro-3-(6-(4-(bicyclo[1.1.1]penta-1-ylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

474.2

TABLE 1-10 Ex. No. IUPAC name structural formula salt MS 431,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-((1-methylcyclopropyl)carbamoyl)-benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

462.2 441,5-anhydro-3-(6-(4-(cyclopropylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

448.2 451,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-((tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol

492.3 461,5-anhydro-2,3-dideoxy-3-(6-(4-((3-fluorocyclobutyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

480.2 471,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-((2-(morpholin-4-yl)ethyl)carbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

521.3

TABLE 1-11 Ex. No. IUPAC name structural formula salt MS 481,5-anhydro-2,3-dideoxy-3-(6-(4-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

480.2 491,5-anhydro-2,3-dideoxy-3-(6-(4-((2-methoxyethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

466.1 501,5-anhydro-2,3-dideoxy-3-(6-(4-((2-hydroxyethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

452.2 511,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-((tetrahydro-2H-pyran-4-ylmethyl)carbamoyl)-benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol

506.3 521,5-anhydro-2,3-dideoxy-3-(6-(4-((3-(difluoromethyl)azetidin-1-yl)carbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

498.2

TABLE 1-12 Ex. No. IUPAC name structural formula salt MS 531,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-((3,3,3-trifluoropropyl)carbamoyl)-benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol

504.2 541,5-anhydro-3-(8-chloro-7-methyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

467.1 551,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol

441.1 561,5-anhydro-3-(6-((6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

472.2 571,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methoxy-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

442.1

TABLE 1-13 Ex. No. IUPAC name structural formula salt MS 581,5-anhydro-2,3-dideoxy-3-(7-methoxy-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

448.1 59 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol

447.1 601,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

427.2 611,5-anhydro-2,3-dideoxy-3-(7-methoxy-6-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

447.1 62 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol

448

TABLE 1-14 Ex. No. IUPAC name structural formula salt MS 631,5-anhydro-2,3-dideoxy-3-(7-methoxy-6-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

448.1 64 1,5-anhydro-2,3-dideoxy-3-(7-methoxy-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

449.1 65 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((3-methyloxetan-3-yl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

496.1 66 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(2-methoxyethyl)benzamide

484.2

TABLE 1-15 Ex. No. IUPAC name structural formula salt MS 671,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((2-fluoroethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

472.2 68 1,5-anhydro-2,3-dideoxy-3-(6-(4-((2-(dimethylamino)-2-oxoethyl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

511.2 691,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-D-threo-pentitol

440.1 70 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((3-(methylsulfonyl)propyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

546.2

TABLE 1-16 Ex. No. IUPAC name structural formula salt MS 711,5-anhydro-3-(6-( (6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(synonym)6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

486.2 721,5-anhydro-3-(6-((6-(1-tert-butyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(synonym)6-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

488.2 73 1,5-anhydro-2,3-dideoxy-3-(6-((6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-((6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethylquinazolin-4(3H)-one

490.2

TABLE 1-17 Ex. No. IUPAC name structural formula salt MS 741,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol(synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

514.1 75 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol(synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

516.2 76 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(((1-hydroxycyclopropyl)methyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

496.1 77 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((2-(2-oxopyrrolidin-1-yl)ethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

537.2

TABLE 1-18 Ex. No. IUPAC name structural formula salt MS 781,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

523.2 79 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((oxetan-3-ylmethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

496.2 80 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

510.2 81 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(((2R)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(((R)-tetrahydrofuran-2-yl)methyl)benzamide

510.2

TABLE 1-19 Ex. No. IUPAC name structural formula salt MS 821,5-anhydro-2,3-dideoxy-3-(6-((6-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

517.2 83 1,5-anhydro-2,3-dideoxy-3-(6-(4-((1,1-dioxidethietan-3-yl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

530.1 84 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((2-(methylsulfonyl)ethyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

532.1 85 1,5-anhydro-2,3-dideoxy-3-(6-(4-((2-ethoxyethyl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(synonym) N-(2-ethoxyethyl)-2-fluoro-4-( (3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide

498.2

TABLE 1-20 Ex. No. IUPAC name structural formula salt MS 861,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((3-methoxypropyl)carbamoyl)-benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol(synonym) 2-fluoro-4-((3-((3R4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(3-methoxypropyl)benzamide

498.1 871,5-anhydro-3-(6-(4-(cyclopropylcarbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol(synonym) N-cyclopropyl-2-fluoro-4-( (3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide

466.1 88 2-fluoro-N-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-4- ((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide

526.2 891,5-anhydro-3-(6-(4-((1-cyanocyclopropyl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

491.2

TABLE 1-21 Ex. No. IUPAC name structural formula salt MS 901,5-anhydro-3-(6-((6-carboxypyridin-3-yl)methyl)-7,8-dimethyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

411.1 91 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(methylcarbamoyl)pyridin-3-yl)methyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol

424 921,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (diastereomeric mixture)

458.1 931,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (epimer of Example 94)

458.1 941,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (epimer of Example 93)

458.1

Comparative Example 1

3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-(4-(1H-pyrazol-1-yl)benzyl)quinazolin-4(3H)-oneSynonym:1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)quinazolin-3(4H)-yl)-L-threo-pentitolA) 2-amino-5-bromo-3,4-dimethylbenzoic Acid

To a solution of 2-amino-3,4-dimethylbenzoic acid ( 2.0 g) in DMSO (25mL) was added hydrobromic acid (48% v/v, 10.2 g) under water cooling,and the mixture was stirred at room temperature for 48 hr. To thereaction mixture was added water (25 mL), and the mixture was cooled at0° C. for 10 min. The precipitate was collected by filtration, washedwith water, and dried under reduced pressure to give the title compound( 2.41 g) •

MS: [M-H] ⁻ 242.0, 244.0.

B) Methyl 2-amino-5-bromo-3,4-dimethylbenzoate

To a mixed solution of 2-amino-5-bromo-3,4-dimethylbenzoic acid ( 3.0 g)and DMF (50 mL) was added cesium carbonate ( 6.01 g), and the mixturewas stirred at room temperature for 30 min. To the reaction solution wasadded methyl iodide ( 2.09 g), and the mixture was stirred at roomtemperature overnight. To the reaction mixture was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water, and dried over anhydrous magnesium sulfate and the solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate/hexane) to give thetitle compound ( 3.0 g).

MS: [M+H]⁺ 257.8, 259.8

C) Methyl2-amino-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a mixture of methyl 2-amino-5-bromo-3,4-dimethylbenzoate ( 3.7 g),bis(pinacolato)diboron ( 7.28 g), potassium acetate ( 4.22 g) andtoluene (100 mL) was added bis(triphenylphosphine)palladium(II) chloride( 1.01 g), and the mixture was stirred under an argon atmosphere at 110°C. overnight. Insoluble material was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate/hexane) and triturated withethyl acetate-hexane to give the title compound ( 0.7 g).

MS: [M+H]⁺ 306.0

D) Methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-3,4-dimethylbenzoate

To a mixture of methyl2-amino-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate( 0.69 g), 1-(4-(chloromethyl)phenyl)-1H-pyrazole (0.46 g), 2 M aqueoussodium carbonate solution ( 2.26 mL) and DME (20 mL) was added (1,1-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethaneadduct ( 0.09 g) under an argon atmosphere and the mixture was stirredat 80° C. overnight. The reaction mixture was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate/hexane) togive the title compound ( 0.65 g).

MS: [M+H]⁺ 336.1

E) 5-(1H-pyrazol-1-yl)benzyl)-2-amino-3,4-dimethylbenzoic acid

To a mixed solution of methyl5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-3,4-dimethylbenzoate ( 0.65 g) andTHF (5 mL)-methanol (5 mL) was added 8 M aqueous sodium hydroxidesolution ( 2.42 mL), and the mixture was stirred at 60° C. for 5 hr. Thereaction mixture was adjusted with 6 M hydrochloric acid to pH 4 underice-cooling. The resulting precipitate was collected by filtration,washed with water and dried under reduced pressure to give the titlecompound ( 0.51 g).

MS: [M+H]⁺ 322.1

F) 5- ( 4- (1H-pyrazol-1-yl) Benzyl) -2-amino-N- ( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3,4-dimethylbenzamide

To a mixture of5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-3,4-dimethylbenzoic acid ( 0.50g), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride ( 0.25 g), WSChydrochloride ( 0.36 g), HOBt monohydrate ( 0.26 g) and DMF (3 mL) wasadded triethylamine ( 0.32 g), and the mixture was stirred at roomtemperature for 4 hr. To the reaction mixture was added water, and theprecipitate was collected by filtration, washed with water and driedunder reduced pressure to give the title compound ( 0.65 g).

MS: [M+H]⁺ 421.2

G) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6- ( 4-(1H-pyrazol-1-yl) benzyl) quinazolin-4 (3H) -one Synonym:1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol

A mixture of 5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3,4-dimethylbenzamide (0.50g) and N,N-dimethylformamide dimethyl acetal ( 1.6 mL) was stirred at90° C. for 4 hr. The reaction mixture was concentrated under reducedpressure, water was added to the residue, and the mixture was stirred atroom temperature for 10 min. The precipitate was collected byfiltration, washed with water and dried under reduced pressure. Theobtained solid was purified by silica gel column chromatography (ethylacetate/hexane) and triturated with ethyl acetate to give the titlecompound ( 0.22 g).

¹H NMR (300 MHz, DMSO-d₆) δ1.78-1.91 (1H, m), 2.08-2.24 (1H, m), 2.29(3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.35-3.49 (1H, m),3.85-4.00 (2H, m), 4.02-4.15 (1H, m), 4.19 (2H, s), 4.41-4.61 (1H, m),5.23 (1H, d, J = 5.5 Hz), 6.50-6.53 (1H, m), 7.20-7.29 (2H, m), 7.71(1H, d, J = 1.7 Hz), 7.72-7.77 (2H, m), 7.84 (1H, s), 8.39-8.48 (2H, m).

Comparative Example 2

3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-(4-(1H-pyrazol-1-yl)benzyl)-1,2,3-benzotriazin-4(3H)-oneSynonym:1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol

To a mixture of 5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3,4-dimethylbenzamide ( 0.15g) and 2 M hydrochloric acid ( 1.07 mL) was added dropwise underice-cooling a solution of sodium nitrite ( 0.03 g) in water ( 1.0 mL),and the mixture was stirred at room temperature for 3 hr. The reactionmixture was neutralized with 8 M aqueous sodium hydroxide solution underice-cooling, and the precipitate was collected by filtration. Theobtained solid was further purified by silica gel column chromatography(ethyl acetate/hexane) and triturated with ethyl acetate to give thetitle compound ( 0.15 g).

¹H NMR (300 MHz, DMSO-d₆) δ1.93 (1H, dd, J = 12.8, 4.3 Hz), 2.13 (1H,qd, J = 12.5, 4.6 Hz), 2.38 (3H, s), 2.76 (3H, s), 3.20 (1H, t, J = 10.7Hz), 3.44-3.56 (1H, m), 3.88-4.01 (2H, m), 4.10 (1H, ddt, J = 15.1,10.1, 5.0 Hz), 4.30 (2H, s), 4.97 (1H, ddd, J = 11.9, 9.8, 4.5 Hz), 5.21(1H, d, J = 5.1 Hz), 6.52 (1H, dd, J = 2.5, 1.7 Hz), 7.22-7.30 (2H, m),7.71 (1H, d, J = 1.3 Hz), 7.74-7.81 (2H, m), 7.93 (1H, s), 8.44 (1H, dd,J = 2.5, 0.4 Hz).

Example 1 Formulation (1) compound obtained in Example 1 10.0 g (2)Lactose 60.0 g (3) Cornstarch 35.0 g (4) Gelatin 3.0 g (5) Magnesiumstearate 2.0 g

A mixture of the compound ( 10.0 g) obtained in Example 1, lactose (60.0 g) and cornstarch ( 35.0 g) is passed through a 1 mm mesh sieve andgranulated by using 10 wt% aqueous gelatin solution (30 mL) ( 3.0 g asgelatin) and the granules are dried at 40° C. and sieved again. Theobtained granules are mixed with magnesium stearate ( 2.0 g) and themixture is compressed. The obtained core tablets are coated with a sugarcoating of an aqueous suspension of sucrose, titanium dioxide, talc andgum arabic. The coated tablets are glazed with beeswax to give 1000coated tablets.

Example 2 Formulation (1) compound obtained in Example 1 10.0 g (2)Lactose 70.0 g (3) Cornstarch 50.0 g (4) Soluble starch 7.0 g (5)Magnesium stearate 3.0 g

The compound ( 10.0 g) obtained in Example 1 and magnesium stearate (3.0 g) are granulated using aqueous soluble starch solution (70 mL) (7.0 g as soluble starch), dried and mixed with lactose ( 70.0 g) andcornstarch ( 50.0 g). The mixture is compressed to give 1000 tablets.

Experimental Example 1 Measurement of M1 Receptor Positive AllostericModulator (M1PAM) Activity

The activity of a test compound in the presence of acetylcholine at EC20concentration (final concentration 0.8-1.0 nM), which affords an actioncorresponding to about 20% of the maximum activity, was measured as PAMactivity. The method is as follows. CHO-K1 cells stably expressing ahuman M1 receptor (hCHRM1) were plated on a 384-well black clear bottomplate (BD Falcon) at 5,000 cells/well, and cultured in an incubator at37° C., 5% CO₂ for 1 day. The medium in the cell plate was removed, andassay buffer A containing calcium indicator (Recording medium (DOJINDOLABORATORIES), 0.1% BSA (Wako Pure Chemical Industries, Ltd.), 2.5 µg/mLFluo-4 AM (DOJINDO LABORATORIES), 0.08% Pluronic F127 (DOJINDOLABORATORIES), 1.25 mM probenecid (DOJINDO LABORATORIES)) was added at30 µL/well. The cells were left standing in the incubator at 37° C., 5%CO₂ for 30 min, and further left standing at room temperature for 30min. A test compound prepared by diluting with assay buffer B (HBSS(Invitrogen), 20 mM HEPES (Invitrogen), 0.1% BSA) containing 3.2-4.0 nMacetylcholine was added at 10 µL/well, and the fluorescence was measuredby FDSS/µCELL (Hamamatsu Photonics K.K.) for 1 min every for 1 second.With the definition that the amount of change in the fluorescence onaddition of acetylcholine (final concentration 1 µM) is 100% and that onaddition of DMSO instead of a test compound is 0%, the activity (%) ofthe test compound was calculated, and the inflection point in theconcentrationdependent curve of the test compound was calculated as IPvalues. The results are shown in Table 2.

TABLE 2-1 Ex. No. IP value (nM) activity (%) at 10 µM 1 2.1 101 2 1.5104 3 1.0 103 4 2.0 101 5 1.5 97 6 0.96 99 8 1.4 97 9 3.3 109 11 0.91100 13 1.0 101 18 1.0 106 19 1.6 103 24 3.7 108 25 1.9 109 27 1.4 110 291.6 112 33 1.8 111 39 3.3 112 41 11 108 49 1.1 101 50 0.80 103 54 0.99106

TABLE 2-2 Ex. No. IP value (nM) activity (%) at 10 µM 56 2.1 107 58 1.9103 59 2.6 108 61 2.2 108 62 2.5 107 65 3.0 109 66 1.8 106 68 1.7 106 712.5 107 73 1.4 109 75 3.0 108 76 1.9 106 77 2.0 107 79 1.5 108 80 1.9107 81 3.7 110 83 1.5 109 84 1.9 106 85 2.1 107 86 3.1 110 87 2.3 111

Experimental Example 2 Mouse Defecation Experiment

Male ICR mice (6-7 weeks old) were used after an acclimation period forabout 1 week. A test drug (1 mg/kg or 3 mg/kg) was suspended in 0.5%methylcellulose solution and orally administered at a volume of 10mL/kg, and the number of feces 2 hr later was counted. Only 0.5%methylcellulose was administered to a solvent administration group.

The results are shown in Table 3. The results show mean ± standarderror.

TABLE 3 Ex. No. dose solvent administration group 0 mg/kg 1 mg/kg 3mg/kg 2 number of feces 2 hr later 4.2±1.2 5.0±0.7 11.3±0.6 3 number offeces 2 hr later 3.71±1.0 14.0±1.0 - 5 number of feces 2 hr later1.81±0.6 5.61±1.0 8.4±2.6 6 number of feces 2 hr later 1.81±0.6 7.2±1.88.2±1.0 19 number of feces 2 hr later 2.6±0.8 12.6±1.2 - 66 number offeces 2 hr later 4.0±1.0 9.3±1.2 -

Experimental Example 3 Mouse PK Test

As the mouse, 8-week-old male ICR mice (Japan SLC, Inc.) were used. Theywere fed on a solid commercially available diet (CE-2, CLEA Japan, Inc.)and allowed to freely ingest tap water as the drinking water. Anintravenous administration solution for the mice was prepared byweighing a test compound, dissolving same in dimethylacetamide (DMA)(Wako Pure Chemical Industries, Ltd.), adding the same volume of1,3-butanediol (Wako Pure Chemical Industries, Ltd.) and mixing bystirring to give a DMA:1,3-butanediol (1:1, v/v) solution. An oraladministration solution was prepared by weighing a test compound,pulverizing same in an agate mortar, and gradually adding 0.5 w/v%aqueous methylcellulose solution to give a suspension. For intravenousadministration, the solution was administered into femoral vein of themice at 0.1 mg/mL/kg (salt converted to free form). For oraladministration, the suspension was administered to the mice at 1 mg/5mL/kg (salt converted to free form). The cassette dosing method was usedfor the both administration routes, and the test compound wasadministered in the following manner.

-   Compound of Example 2 (intravenous: 4 compounds cassette    administration, oral: 4 compounds cassette administration)-   Compound of Example 3 (intravenous: 10 compounds cassette    administration, oral: 5 compounds cassette administration)-   Compound of Example 5 (intravenous: 5 compounds cassette    administration, oral: 5 compounds cassette administration)-   Compound of Example 6 (intravenous: 9 compounds cassette    administration, oral: 5 compounds cassette administration)-   Compound of Example 19 (intravenous: 5 compounds cassette    administration, oral: 5 compounds cassette administration)-   Compound of Example 66 (intravenous: 10 compounds cassette    administration, oral: 5 compounds cassette administration)-   Compound of Example 81 (intravenous: 10 compounds cassette    administration, oral: 5 compounds cassette administration)

In the case of intravenous administration, blood samples were collectedfrom the tail vein at 5, 10, 15, 30 min, 1, 2, 4, 8 hr afteradministration, an anticoagulation treatment with heparin sodium(Shimizu Pharmaceutical Co., Ltd.) was performed, and plasma wascollected after centrifugation and subjected to the measurement of drugconcentration. In the case of oral administration, blood samples werecollected from the tail vein at 15, 30 min, 1, 2, 4, 8 hr afteradministration, an anticoagulation treatment with heparin sodium wasperformed, and plasma was collected after centrifugation and subjectedto the measurement of drug concentration.

All drug concentrations were measured by LC-MS/MS analysis. For apharmacokinetics test, the plasma (5 µL) was placed in a tube,acetonitrile (115 µL) containing internal standard solution was addedand they were mixed on a vortex mixer. Thereafter, the mixture wascentrifuged (5000 rpm, 5 min, 4° C.). The supernatant (100 µL) aftercentrifugation was added to 10 mmol/L ammonium formate (100 µL) addedearlier and mixed therewith. This sample was injected to LC/MS/MS. TheHPLC system used was Shimadzu LC-20A (Shimadzu Corporation), the columnused was Unison UK-C18 HT ( 3.0 µm, 2.0 × 20 mm, Imtakt) at 50° C., and10 mmol/L ammonium formate, 0.2% formic acid as mobile phase A andacetonitrile, 0.2% formic acid as mobile phase B were fed each at a flowrate of 1.2 mL/min under gradient conditions of (B concentration: 0 min→0.1 min, 5%, 0.1→ 0.75 min, 5-99%, 0.75→ 1.15 min, 99%, 1.15→ 1.16 min,5%, 1.16→ 1.5 min, 5%). MS/MS used was AB Sciex TQ5500-MPX (AppliedBiosystems).

The results are shown in Table 4.

-   Tmax: time to reach maximum plasma concentration-   MRT: mean residence time-   iv: intravenous administration-   CL total: total clearance

TABLE 4 Example No. Tmax (h) MRT iv (h) CL total (mL/h/kg) 2 1.0 1.0 6573 1.7 1.9 609 5 0.7 1.2 447 6 1.7 1.4 273 19 1.7 2.5 274 66 0.7 0.8 159881 0.5 0.5 4329

Experimental Example 4 MDR1 Membrane Permeability Test

When MDR1 is expressed in excess in LLC-PK1 cell, which is a polar cell,MDR1 is localized in apical membrane (A), thus promoting transcellulartransport from the basement membrane side (B) toward direction A. When aratio to the transcellular transport in the opposite direction is takenand a ratio to a control cell in which a mock vector has been introducedis further taken, an efflux ratio of MDR1 to simple diffusion (correctedefflux ratio) is calculated. Similarly, when a brain/plasmaconcentration ratio in Mdr1(-/-) mouse is divided by a brain/plasmaconcentration ratio in wild-type mouse, an efflux ratio of Mdr1 tosimple diffusion in BBB (Kp, brain ratio, higher value means lowercentral nervous system permeability) is calculated. Adachi Y. et al.(Reference 1) has reported a positive correlation between correctedefflux ratio and Kp, brain ratio (Fig. 5(C)), and efflux ratio in MDR1expressing cell and Kp, brain ratio (Fig. 5(B)). That is, the reportshows that a higher efflux ratio of MDR1 in vitro results in lowercentral nervous system permeability.

To confirm the central nervous system permeability of the compounds ofthe present invention, a MDR1 membrane permeability test was performedby the following method.

Digoxin and lucifer yellow (LY) were purchased from Sigma-Aldrich,Diclofenac, colchicine and alprenolol were purchased from Wako PureChemical Industries, Ltd., and other reagents used were commerciallyavailable products of special grade.

Human MDR1-expressing LLC-PK1 cells were cultured according to thereport of Takeuchi et al. (Reference 2). Human MDR1-expressing LLC-PK1cells were cultured in 10% fetal bovine serum (Invitrogen), 500 µg/mlG418 (Invitrogen), 150 ng/ml colchicine-containing M199 medium(Invitrogen) under 5% CO₂ conditions at 37° C.

Transcellular transport was performed according to the report ofSugimoto et al. (Reference 3). The cells were cultured for 3 days on HTSTranswell (registered trademark) 96 well permeable support (pore size0.4 µm, 0.143 cm² surface area, Corning Life Sciences) havingpolyethylene terephthalate membrane on which the cells had been seededat 3.45 × 10⁴ cells/well. After preincubation in M199 medium (containing10 mmol/L HEPES, 1% BSA, pH 7.4) for 30 min, a drug solution (10 µmol/Ldigoxin, 200 µmol/L LY, 10 µmol/L test compound) dissolved in M199medium was added to the apical side or basolateral side of the Transwellby 75 or 250 µL each and the cells were cultured under 5% CO₂ conditionsat 37° C. After 1 hr, the sample was collected from the side opposite tothe side where the drug solution was added, and the concentration of thetest compound was measured by LC-MS/MS. As an internal standardsubstance, 100 ng/mL alprenolol and diclofenac were used. The analysisconditions were as follows.

-   LC: UFLC LC-20 (Shimadzu)-   MS/MS: API4000 (AB Sciex Instruments)-   LC condition: gradient method

TABLE 5 Time (min) Pump B (%) 0.02 5 0.40 95 0.80 95 0.81 5 1.50 Stop

-   Column: Unison UK-C18 HT ( 3.0 µm, 2.0 × 20 mm)-   Column temperature: 50° C.-   Flow rate: 0.7 mL/min (for 1.5 min run), 1.0 mL/min (for 1.0 min    run)-   Mobile phase A: 50 mM CH₃COONH₄:MeCN:water = 1:1:8-   Mobile phase B: 50 mM CH₃COONH₄:MeCN = 1:9-   Injection volume: 1-20 µL

LY was measured by a fluorescence plate reader (Fluoroskan Ascent FL).

P_(app), A to B and P_(app), B to A (apparent permeability) werecalculated from the formula (1), and the efflux ratio (ER) wascalculated from the formula (2).

$\begin{matrix}{P_{\text{app}} = \frac{\text{Amount}}{\text{Area} \times \text{C}_{0} \times \text{Time}}} & \text{­­­(1)}\end{matrix}$

-   Amount: amount of transported digoxin/well-   Area: surface area of cell monolayer ( 0.143 cm² )-   C₀: concentration of drug solution added-   Time: incubation time

$\begin{matrix}{ER = \frac{\text{P}_{\text{app}},\text{B to A}}{\text{P}_{\text{app}},\text{A to B}}} & \text{­­­(2)}\end{matrix}$

The results are shown in Table 6.

TABLE 6-1 Example No. MDR1 substrate screening 1 µM (MDRSUB1)/Ratio(NUMBER) Comparative Example 1 0.83 Comparative Example 2 1.3 1 4.7 2 183 6 4 5.7 5 15 6 11 7 3.5 8 4.8 9 2.1 10 15 11 17 12 17 13 38 14 22 159.7 16 6.8 18 24 19 4.6 20 2.9 21 20 22 12 23 19 24 3.4 25 16 26 24 2723 28 11 29 12 30 24

TABLE 6-2 Example No. MDR1 substrate screening 1 µM (MDRSUB1)/Ratio(NUMBER) 31 12 32 26 33 20 34 20 35 9 36 11 37 12 38 15 40 12 41 13 425.9 43 12 44 22 45 23 46 18 47 24 48 24 49 20 50 13 51 27 52 18 53 8.354 9.5 55 3.2 56 4.9 57 16 58 19 59 3.7

TABLE 6-3 Example No. MDR1 substrate screening 1 µM (MDRSUB1)/Ratio(NUMBER) 61 32 62 9.4 63 35 64 36 65 15 66 7 67 5.3 68 19 70 13 71 8 722.9 73 18 74 7.1 75 13 76 15 77 32 78 56 79 26 80 9.5 81 8.6 82 >18 8319 84 11 85 10 86 7.8 87 8.7 88 16 89 16 91 5.9

Experimental Example 5 Rat Defecation Experiment

Male SD rats (5-6 weeks old) were used after an acclimation period forabout 1 week. A test drug (1 mg/kg, 3 mg/kg, or 10 mg/kg) was suspendedin 0.5% methylcellulose solution and orally administered at a volume of5 mL/kg, and the number of feces 2 hr later was counted. Only 0.5%methylcellulose was administered to a solvent administration group.

The results are shown in Table 7. The results show mean ± standarderror.

TABLE 7 Ex. No. dose solvent administration group 0 mg/kg 1 mg/kg 3mg/kg 10 mg/kg 3 number of feces 2 hr later 3.4±1.0 7.4±0.7 7.8±1.4 - 66number of feces 2 hr later 3.6±0.4 9.9±1.0 - - 81 number of feces 2 hrlater 5.1±0.7 6.9±1.1 7.0±0.8 11.5+1.1

REFERENCES

-   1. Adachi Y. et al., Comparative studies on in vitro methods for    evaluating in vivo function of MDR1 P-glycoprotein, Pharm. Res.    18:1660-1668, 2001-   2. Takeuchi T., Yoshitomi S., Higuchi T., Ikemoto K., Niwa S.,    Ebihara T., Katoh M., Yokoi T. and Asahi S., Establishment and    characterization of the transformants stably-expressing MDR1 derived    from various animal species in LLC-PK1, Pharm. Res.,    23(7):1460-1472, 2006-   3. Sugimoto H., Hirabayashi H., Kimura Y., Furuta A., Amano N. and    Moriwaki T., Quantitative investigation of the impact of    P-glycoprotein inhibition on drug transport across blood-brain    barrier in rats, Drug Metab. Dispos., 39(1):8-14, 2011

INDUSTRIAL APPLICABILITY

The compound of the present invention may have a cholinergic muscarinicM1 receptor positive allosteric modulator activity and may be useful asa medicament such as an agent for the prophylaxis or treatment ofconstipation and the like.

This application is based on patent application No. 2017-81919 filed inJapan, the entire contents of which are incorporated by referenceherein.

1. A compound represented by the formula (I):

wherein X¹ is CH or N; X² is CR¹⁰ or N; R¹⁰ is a hydrogen atom or ahalogen atom; R¹ and R² are each independently a hydrogen atom, ahalogen atom, an optionally substituted C₁₋₆ alkyl group or anoptionally substituted C₁₋₆ alkoxy group; R³ and R⁴ are eachindependently a hydrogen atom, a halogen atom, a hydroxy group, anoptionally substituted C₁₋₆ alkyl group or an optionally substitutedC₁₋₆ alkoxy group; R⁵ and R⁶ are each independently a hydrogen atom or ahalogen atom; R⁷ is a substituted monocyclic heterocyclic group, anoptionally substituted carbamoyl group, an optionally substituted C₁₋₆alkyl group, a carboxy group, a substituted C₁₋₆ alkoxy group, anoptionally substituted heteroaryloxy group or a group represented byN(R⁸)COR⁹ wherein R⁸ is a hydrogen atom or an optionally substitutedC₁₋₆ alkyl group and R⁹ is an optionally substituted C₁₋₆ alkyl group,or a salt thereof.
 2. The compound according to claim 1, wherein R¹ is ahydrogen atom, a halogen atom or a C₁₋₆ alkyl group; R² is a C₁₋₆ alkylgroup or a C₁₋₆ alkoxy group; R³ and R⁴ are each independently ahydrogen atom or a halogen atom; R⁵ and R⁶ are each independently ahydrogen atom or a halogen atom; and R⁷ is (1) a 5- or 6-memberedmonocyclic aromatic heterocyclic group substituted by 1 to 3substituents selected from (a) a C₁₋₆ alkyl group optionally substitutedby 1 to 3 substituents selected from a halogen atom, a C₃₋₁₀ cycloalkylgroup, a C₁₋₆ alkoxy group and a mono- or di-C₁₋₆ alkyl-carbamoyl group,(b) a C₃₋₁₀ cycloalkyl group, and (c) a 3- to 8-membered monocyclicnon-aromatic heterocyclic group, (2) a carbamoyl group substituted by 1or 2 substituents selected from (a) a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 substituents selected from (i) a halogen atom,(ii) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3 hydroxygroups, (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group, (iv) a C₁₋₆alkoxy group, (v) a hydroxy group, (vi) a 3- to 8-membered monocyclicnon-aromatic heterocyclic group optionally substituted by one oxo group,and (vii) a C₁₋₆ alkylsulfonyl group, (b) a C₃₋₁₀ cycloalkyl groupoptionally substituted by 1 to 3 substituents selected from a halogenatom, an optionally halogenated C₁₋₆ alkyl group and a cyano group, and(c) a 3- to 8-membered monocyclic non-aromatic heterocyclic groupoptionally substituted by 1 to 3 substituents selected from a C₁₋₆ alkylgroup, an oxo group and a hydroxy group, (3) an azetidin-1-ylcarbonylgroup optionally substituted by 1 to 3 substituents selected from anoptionally halogenated C₁₋₆ alkyl group, a hydroxy group and a C₁₋₆alkoxy group, (4) a C₁₋₆ alkyl group, or (5) a carboxy group, or a saltthereof.
 3. The compound according to claim 1, wherein R⁷ is a carbamoylgroup substituted by 1 or 2 substituents selected from (a) a C₁₋₆ alkylgroup optionally substituted by 1 to 3 substituents selected from (i) ahalogen atom, (ii) a C₃₋₁₀ cycloalkyl group optionally substituted by 1to 3 hydroxy groups, (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(iv) a C₁₋₆ alkoxy group, (v) a hydroxy group, (vi) a 3- to 8-memberedmonocyclic non-aromatic heterocyclic group optionally substituted by oneoxo group, and (vii) a C₁₋₆ alkylsulfonyl group, (b) a C₃₋₁₀ cycloalkylgroup optionally substituted by 1 to 3 substituents selected from ahalogen atom, an optionally halogenated C₁₋₆ alkyl group and a cyanogroup, and (c) a 3- to 8-membered monocyclic non-aromatic heterocyclicgroup optionally substituted by 1 to 3 substituents selected from a C₁₋₆alkyl group, an oxo group and a hydroxy group, or a salt thereof.
 4. Thecompound according to claim 1, wherein R¹ is a halogen atom or a C₁₋₆alkyl group; R² is a C₁₋₆ alkyl group; R³ is a hydrogen atom; R⁴ is ahydrogen atom; R⁵ is a hydrogen atom; R⁶ is a hydrogen atom or a halogenatom; and R⁷ is (1) a 5- or 6-membered monocyclic aromatic heterocyclicgroup substituted by 1 to 3 substituents selected from (a) a C₁₋₆ alkylgroup optionally substituted by 1 to 3 substituents selected from aC₃₋₁₀ cycloalkyl group and a C₁₋₆ alkoxy group, (b) a C₃₋₁₀ cycloalkylgroup, and (c) a 3- to 8-membered monocyclic non-aromatic heterocyclicgroup, (2) a carbamoyl group substituted by 1 or 2 substituents selectedfrom (a) a C₁₋₆ alkyl group optionally substituted by 1 to 3substituents selected from (i) a C₃₋₁₀ cycloalkyl group optionallysubstituted by 1 to 3 hydroxy groups, (ii) a mono- or di-C₁₋₆alkyl-carbamoyl group, (iii) a C₁₋₆ alkoxy group, (iv) a hydroxy group,(v) a 3- to 8-membered monocyclic non-aromatic heterocyclic groupoptionally substituted by one oxo group, and (vi) a C₁₋₆ alkylsulfonylgroup, (b) a C₃₋₁₀ cycloalkyl group optionally substituted by 1 to 3halogen atoms, and (c) a 3- to 8-membered monocyclic non-aromaticheterocyclic group optionally substituted by 1 to 3 substituentsselected from a C₁₋₆ alkyl group and an oxo group, or (3) anazetidin-1-ylcarbonyl group optionally substituted by 1 to 3 C₁₋₆ alkoxygroups, or a salt thereof.
 5. The compound according to claim 1, whereinR¹ is a halogen atom or a C₁₋₆ alkyl group; R² is a C₁₋₆ alkyl group; R³is a hydrogen atom; R⁴ is a hydrogen atom; R⁵ is a hydrogen atom; R⁶ isa hydrogen atom or a halogen atom; and R⁷ is (1) a 5- or 6-memberedmonocyclic aromatic heterocyclic group substituted by 1 to 3 C₁₋₆ alkylgroups, or (2) a carbamoyl group substituted by a C₁₋₆ alkyl groupoptionally substituted by one substituent selected from a C₁₋₆ alkoxygroup and a 3- to 8-membered monocyclic non-aromatic heterocyclic group,or a salt thereof. 6.3-((3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one,or a salt thereof. 7.2-Fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-methylbenzamide,or a salt thereof. 8.6-((6-(1,3-Dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one,or a salt thereof. 9.3-((3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one,or a salt thereof. 10.4-((8-Chloro-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)methyl)-2-fluoro-N-methylbenzamide, or a saltthereof. 11.2-Fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(2-methoxyethyl)benzamide,or a salt thereof.
 12. (canceled)
 13. A medicament comprising thecompound according to claim 1 or a salt thereof.
 14. The medicamentaccording to claim 13, which is a cholinergic muscarinic M1 receptorpositive allosteric modulator.
 15. The medicament according to claim 13,which is a prophylactic or therapeutic agent for constipation.
 16. Amethod of cholinergic muscarinic M1 receptor positive allostericmodulation in a mammal, comprising administering an effective amount ofthe compound according to claim 1 or a salt thereof to said mammal. 17.A method for the prophylaxis or treatment of constipation in a mammal,comprising administering an effective amount of the compound accordingto claim 1 or a salt thereof to the mammal. 18-19. (canceled)
 20. Thecompound according to claim 2, wherein R⁷ is a carbamoyl groupsubstituted by 1 or 2 substituents selected from (a) a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 substituents selected from (i) ahalogen atom, (ii) a C₃₋₁₀ cycloalkyl group optionally substituted by 1to 3 hydroxy groups, (iii) a mono- or di-C₁₋₆ alkyl-carbamoyl group,(iv) a C₁₋₆ alkoxy group, (v) a hydroxy group, (vi) a 3- to 8-memberedmonocyclic non-aromatic heterocyclic group optionally substituted by oneoxo group, and (vii) a C₁₋₆ alkylsulfonyl group, (b) a C₃₋₁₀ cycloalkylgroup optionally substituted by 1 to 3 substituents selected from ahalogen atom, an optionally halogenated C₁₋₆ alkyl group and a cyanogroup, and (c) a 3- to 8-membered monocyclic non-aromatic heterocyclicgroup optionally substituted by 1 to 3 substituents selected from a C₁₋₆alkyl group, an oxo group and a hydroxy group, or a salt thereof.